Thienopyrimidine derivatives

ABSTRACT

This invention provides thienopyrimidine derivatives of the formula, 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1  stands for hydrogen atom, an alkyl group or the like; R 2  stands for a hydrogen atom, an alkyl or amino group or the like, R 3  stands for an alkyl, alkenyl or alkylthio group or the like or a group Y—X—; or R 2  and R 3  may together form tetramethylene group; X standing for a direct bond or linking group such as CH 2 , CH(OH), S, O, NH; Y standing for a substituted or unsubstituted aromatic carbocycylic, aromatic heterocylic, cycloalkyl or saturated heterocyclic group or the like; Z stands for S or O, and n is 0 or an integer of 1 to 4,
 
or salts thereof, which exhibit an inhibitory effect on PDE9, and are therefore useful for prevention or treatment of overactive bladder syndrome, pollakiuria, urinary incontinence, dysuria associated with prostatic hyperplasia, urolithiasis, Alzheimer&#39;s disease, chronic obstructive pulmonary disease, myocardial infarction, thrombosis, diabetes and the like.

TECHNICAL FIELD

This invention relates to novel thienopyrimidine derivatives and saltsthereof, which exhibit type 9 phosphodiesterase (PDE9)-inhibitingactivity and are useful as treating agent of dysuria and the like.

BACKGROUND ART

Dysuria can be largely divided into emptying disorder due to inabilityto urinate with sufficient force at the time of emptying the bladder,and bladder-filling disorder due to inability to retain urine during thefilling time. Presently, α₁ blocker is frequently used for treating theemptying disorder and anticholine agent, for treating bladder-fillingdisorder. These drugs, however, have such defects as insufficientlong-term therapeutic effect or reduction in quality of life (QOL)induced by side effect, and development of drugs having new activitymechanism different from the conventional approach, for example, drugsutilizing potassium channel opening activity, cyclicguanosine-3′,5′-monophosphate (cGMP) degradation inhibiting activity,are in demand.

cGMP plays an important role in variegated cellular phenomena such assmooth muscle relaxation, memory and learning function control,photoreaction of retina, cell proliferation, immunoreaction and thelike, and drop in intracellular cGMP concentration causes disorder incell functions. Synthesis of cGMP by nitrogen monoxide (NO)-cGMP systemand degradation of cGMP by PDE system are continually progressing in thecells each at a constant rate and good balance of the two are maintainedin normal cells. Whereas, within the cells under various states ofdisorder, function of the NO-cGMP system lowers to render the cGMPsynthesis level in the cells low. Because the cGMP degradation in thecells progresses at a fixed rate in the meantime, cGMP concentration inthe affected cells becomes low. It is expected, therefore, prevention ofcGMP degradation in the cells to redress the reduction in intracellularcGMP concentration would be useful for treating or preventing diseases.

While there are many types of PDE, those which specifically decomposecGMP are type 5 (PDE5), type 6 (PDE6) and type 9 (PDE9). Of these, PDE9shows the least Km value (J. Biol. Chemistry, Vol. 273, No. 25,15559-15564 (1998), has high affinity to cGMP and is considered toparticipate in degradation of cGMP with particular significance.

Heretofore, pyrazolopyrimidine derivatives are known as the compoundsexhibiting PDE9-inhibiting activity, and as patent literature relatingto the derivatives, for example, there are PCT International PublicationWO 03/037432 Pamphlet disclosing their utility for treatinginsulin-resistant diseases, WO 03/037899 Pamphlet disclosing theirutility for treating cardiovascular disorder, and WO 2004/018474Pamphlet disclosing their utility for improving perception, learning andmemory functions.

Whereas, thienopyrimidine derivatives having PDE9-inhibiting activityare heretofore entirely unknown, and there is no existing literaturediscussing relevancy between PDE9-inhibiting activity and therapeuticeffect on dysuria.

Screening library of Ambinter Co. posts a thienopyrimidine derivativerepresented by the following formula:

but catalogues, pamphlets and the like materials issued by the samecompany give no information including activity on this compound.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide novel thienopyrimidinederivatives which have PDE9-inhibiting action and are useful as treatingagent for disorders including dysuria.

We have discovered, after ardent research activities, that inhibition ofPDE9 is effective for treating dysuria such as overactive bladdersyndrome, pollakiuria, urinary incontinence, dysuria in benign prostatichyperplasia and various diseases relating to urinary tract such asurolithiasis. Based on this discovery, we have created novelthienopyrimidine derivatives having PDE9-inhibiting activity which areuseful as dysuria-treating agent, and come to complete the presentinvention.

According to the present invention, therefore, thienopyrimidinederivatives represented by formula (I)

in which

R¹ stands for hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxyC₁₋₆ alkyl or C₁₋₆haloalkyl containing 1-6 halogen atoms,

R² stands for hydrogen, C₁₋₆ alkyl, phenylC₁₋₆ alkyl or amino,

R³ stands for C₂₋₆ alkyl, C₂₋₆ alkenyl, carbamoylC₁₋₆ alkyl, aminoC₁₋₆alkyl, C₁₋₆ alkylaminoC₁₋₆ alkyl, di-(C₁₋₆ alkyl)aminoC₁₋₆ alkyl, C₁₋₆alkylthio or Y—X— group, or

R² and R³ may together form tetramethylene,

X standing for a direct bond, or CH₂, CH(OH), CH(C₆H₅), CO, CH₂CH₂,CH₂CO, COCH₂, S, O or NH and

Y standing for aromatic carbocyclic group, aromatic heterocyclic group,4-7-membered cycloalkyl group, 4-7-membered cycloalkenyl group,5-7-membered saturated heterocyclic group containing 1 or 2 nitrogenatoms, or 5-7-membered saturated heterocyclic group forming a condensedring with 5 or 6-membered saturated cyclic group and containing 1 or 2nitrogen atoms, all of these groups optionally containing 1-3substituents selected from halogen atom, C₁₋₆ alkyl, C₁₋₆ haloalkylcontaining 1-6 halogen atoms, C₁₋₆ haloalkyloxy containing 1-6 halogenatoms, C₁₋₆ haloalkylthio containing 1-6 halogen atoms, C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₄ alkylenedioxy, carboxyl, C₁₋₆ alkoxycarbonyl, oxo,amino, nitro and phenyl,

Z stands for S or O, and

n is 0 or an integer of 1-4,

with the proviso that a case wherein R¹ is methyl, R² is hydrogen, R³ isbenzyl, Z is O and n is 0 is excluded, or salts of the derivatives areprovided.

In the present specification, the expressions, “C₁₋₆”, “C₁₋₄” and “C₂₋₆”indicate that the carbon numbers in the groups to which theseexpressions are attached are respectively within the range of givennumbers.

“C₁₋₆ alkyl” may be linear or branched, examples of which includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl and n-hexyl. Of these, methyl, ethyl, n-propyl,isopropyl and n-butyl are preferred. Also “C₂₋₆ alkyl” encompasses thosegroups defined as to above C₁₋₆ alkyl except methyl, among which ethyl,n-propyl, isopropyl and n-butyl are preferred.

“C₂₋₆ alkenyl” can have one or plural double bonds at optionalposition(s) and may be linear or branched, of which specific examplesinclude vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,1,3-butadienyl, 2-methylallyl, 1-pentenyl and 1-hexenyl, among whichvinyl, allyl and isopropenyl are preferred.

“C₁₋₆ alkoxy” is oxy (O) group substituted with C₁₋₆ alkyl, of whichspecific examples include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy andn-hexyloxy. Of those, methoxy, ethoxy, n-propoxy, isopropoxy andn-butoxy are preferred.

“C₁₋₆ alkylthio” is thio (S) group substituted with C₁₋₆ alkyl, of whichspecific examples include methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio,n-pentylthio and n-hexylthio. Of those, methylthio, ethylthio,n-propylthio, isopropylthio and n-butylthio are preferred.

“C₁₋₄ alkylenedioxy” includes, for example, methylenedioxy,ethylenedioxy, propylenedioxy and tetramethylenedioxy. Of those,methylenedioxy and ethylenedioxy are preferred.

“4-7-Membered cycloalkyl” includes cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl. Of those, cyclopentyl and cyclohexyl are preferred.

“Halogen atom” includes fluorine, chlorine, bromine and iodine,fluorine, chlorine and bromine being particularly preferred.

“C₁₋₆ haloalkyl containing 1-6 halogen atoms” signifies C₁₋₆ alkylfollowing the earlier given definition, which are substituted with sameor different 1-6 halogen atoms, of which specific examples includefluoromethyl, trifluoromethyl, 1,2-dichloroethyl, 1-chloro-2-bromoethyl,pentafluoroethyl, 1-chloro-n-propyl, 2-bromo-2-methylethyl,3-chloro-n-pentyl and 2-bromo-3-chloro-n-hexyl. Of those, C₁₋₂ alkylsubstituted with same or different 1-5 halogen atoms are preferred.

Also “C₁₋₆ haloalkyloxy containing 1-6 halogen atoms” signifies oxy (O)group substituted with above “C₁₋₆ haloalkyl containing 1-6 halogenatoms”, and “C₁₋₆ haloalkylthio containing 1-6 halogen atoms” signifiesthio (S) group substituted with above “C₁₋₆ haloalkyl containing 1-6halogen atoms”.

“C₁₋₆ alkoxyC₁₋₆ alkyl” in the definition of R¹ in the formula (I)signifies C₁₋₆ alkyl substituted with C₁₋₆ alkoxy following the earliergiven definition, of which specific examples include methoxymethyl,methoxyethyl, methoxy-n-propyl, methoxy-n-butyl, methoxy-n-hexyl,ethoxymethyl, isopropoxymethyl, ethoxyethyl and n-butoxy-n-propyl. Ofthose, methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl arepreferred.

“PhenylC₁₋₆ alkyl” in the definition of R² in the formula (I) signifiesC₁₋₆ alkyl following its definition as given earlier, which issubstituted with phenyl; and “carbamoylC₁₋₆ alkyl”, the C₁₋₆ alkylfollowing the earlier given definition, which is substituted withcarbamoyl (—CONH₂); and “aminoC₁₋₆ alkyl”, the C₁₋₆ alkyl following theearlier given definition, which is substituted with amino (—NH₂).

“C₁₋₆ alkylaminoC₁₋₆ alkyl” in the definition of R³ in the formula (I)signifies the above aminoC₁₋₆ alkyl whose amino group is furthersubstituted with one of C₁₋₆ alkyl groups following the earlier givendefinition; and “di-(C₁₋₆ alkyl)aminoC₁₋₆ alkyl” signifies the same asabove except that the amino group is substituted with two of the C₁₋₆alkyl groups following the earlier given definition. Here the two C₁₋₆alkyl substituting an amino group in di-(C₁₋₆ alkyl)aminoC₁₋₆ alkyl maybe the same or different.

“C₁₋₆ alkylthio” in the definition of R³ signifies thio (S) groupsubstituted with the C₁₋₆ alkyl following the earlier given definition,and “C₁₋₆ alkoxycarbonyl” in the definition of Y in the formula (I)signifies carbonyl (CO) substituted with the C₁₋₆ alkoxy group followingthe earlier given definition.

“Aromatic carbocyclic group” in the definition of Y encompasses C₆₋₂₀aromatic carbocyclic groups, of which specific examples include phenyl,1-indenyl, 1-naphthyl, 2-naphthyl, 2-anthryl and 1-acenaphthenyl. Ofthose, phenyl and 1-naphthyl are preferred.

“Aromatic heterocyclic group” in the definition of Y encompassesmonocyclic or polycyclic aromatic heterocyclic compounds containing 1 or2 hetero atoms selected from N, O and S, of which one ring is 5- or6-membered. Specific examples include pyrrolyl, furyl, thienyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzimidazolyl,benzoxazolyl, benzthiazolyl, quinolyl, isoquinolyl and quinazolyl. Ofthose, monocyclic aromatic heterocyclic groups are preferred.

As “4-7-membered cycloalkenyl” in the definition of Y, for example,1-cyclobutenyl, 1-cyclopentenyl, 1-cyclohexenyl, 1-cycloheptenyl,2-cyclobutenyl, 2-cyclopentenyl and 3-cyclohexenyl can be named. Ofthose, 1-cyclohexenyl and 2-cyclohexenyl are preferred.

As “5-7-membered saturated heterocyclic group containing 1 or 2 nitrogenatoms” in the definition of Y, for example, pyrrolidinyl, piperidinyl,piperazinyl and azepinyl can be named. Of those, piperidinyl andpiperazinyl are preferred.

As “5-7-membered saturated heterocyclic group forming a condensed ringwith 5- or 6-membered saturated cyclic group and containing 1 or 2nitrogen atoms” in the definition of Y, for example,hexahydrocyclopenta[b]pyrrolyl, hexahydrocyclopenta[c]pyrrolyl,octahydrocyclopenta[b]pyridyl, octahydrocyclopenta[b]pyridyl,decahydrocyclopenta[b]azepinyl, octahydroindolyl, octahydroisoindolyl,decahydroquinolyl, decahydroisoquinolyl, dodecahydrobenzo[b]azepinyl,octahydropyrrolo[2,3-d]pyridyl, octahydropyrrolo[1,2-a]pyrazyl,octahydropyrido[1,2-a]pyrimidinyl, decahydrophthalazinyl,decahydronaphthyridinyl and decahydroquinazolinyl can be named. Ofthose, decahydroquinolyl, decahydroisoquinolyl andoctahydropyrrolo[1,2-a]pyrazyl are preferred.

The compound of the formula (I), in which R¹ is methyl, R² is hydrogen,R³ is benzyl, Z is O and n is 0 (which is hereinafter referred to as“Compound A”) has already been posted in the screening library ofAmbinter Co., and therefore it is excluded from the compoundsrepresented by the formula (I) of the present invention. In thisscreening library, however, utility of Compound A is neither describednor suggested.

Accordingly, the present invention also provides PDE9-inhibiting agentscontaining the compounds including thienopyrimidine derivativesrepresented by the formula (I) as well as Compound A (hereafter they arecollectively referred to as “compounds of formula (IA)”) or saltsthereof; pharmaceutical compositions comprising compounds of the formula(IA) or salts thereof and pharmaceutically acceptable carriers; andtreating agents for overactive bladder syndrome, pollakiuria, urinaryincontinence, dysuria in benign prostatic hyperplasia, neurogenicbladder, interstitial cystitis, urolithiasis, benign prostatichyperplasia, erectile dysfunction, cognitive impairment, neuropathy,Alzheimer's disease, pulmonary hypertension, chronic obstructivepulmonary disease, ischemic heart disease, hypertension, angina,myocardial infarction, arteriosclerosis, thrombosis, embolism, type 1diabetes, and type 2 diabetes, which are characterized by containingcompounds of the formula (IA) or salts thereof as the active ingredient.

A group of compounds which are preferred for the present invention arethose of the formula (I) in which R¹ stands for C₁₋₆ alkyl, inparticular, methyl.

Another preferred group of compounds for the present invention are thoseof the formula (I) in which R² stands for hydrogen.

Still another preferred group of compounds for the present invention arethose of the formula (I) in which R³ stands for Y—X—group, inparticular, the compounds of the formula (I) in which X stands for CH₂,S, O or NH, inter alia, CH₂.

Furthermore, where R³ stands for Y—X— group, the compounds of theformula (I) in which Y stands for an aromatic carbocyclic group oraromatic heterocyclic group, which are optionally substituted with 1-3substituents selected from halogen, C₁₋₆ alkyl, C₁₋₆ haloalkylcontaining 1-6 halogen atoms, C₁₋₆ haloalkyloxy containing 1-6 halogenatoms, C₁₋₆ haloalkylthio containing 1-6 halogen atoms, C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₄ alkylenedioxy, carboxyl, C₁₋₆ alkoxycarbonyl,amino, nitro and phenyl, are particularly preferred.

Another preferred group of compounds for the present invention are thoseof the formula (I) in which Z stands for O.

Still different group of compounds preferred for the present inventionare those of the formula (I) in which n is 0.

Typical examples of the compounds of the formula (I) which are providedby the present invention include the following, besides those shown inthe later appearing Examples:

-   2-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid,-   2-(5-chlorothiophen-2-ylmethyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(2-fluorobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(3-fluorobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(4-fluorobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(2-chlorobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(4-chlorobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(3-bromobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(3-methylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   4-oxo-2-(2-trifluoromethylbenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(cyclohexen-1-ylmethyl)-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylic    acid,-   5-methyl-4-oxo-2-(thiophen-2-yl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(α-hydroxythiophen-2-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   5-methyl-4-oxo-2-[(2-thiophen-2-yl)ethyl]-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   5-methyl-4-oxo-2-(thiophen-2-ylcarbonyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   5-methyl-4-oxo-2-(thiophen-2-ylsulfanyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   5-methyl-4-oxo-2-(thiophen-2-yloxy)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylic    acid,-   5-methyl-4-oxo-2-(thiophen-2-ylamino)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(5-fluorothiophen-2-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(5-bromothiophen-2-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   5-methyl-2-(5-methylthiophen-2-ylmethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(5-fluorothiophen-3-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(5-chlorothiophen-3-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(5-bromothiophen-3-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   5-methyl-2-(5-methylthiophen-3-ylmethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(furan-2-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(furan-3-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(5-chlorofuran-2-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(5-chlorofuran-3-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(5-chlorooxazol-2-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   5-methyl-4-oxo-2-(pyridin-4-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   5-methyl-4-oxo-2-(pyrimidin-2-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(4-methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(3,5-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(4-chloro-3-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(4-chloro-3-methylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(4-chloro-3-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(3-chloro-5-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(3-carboxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(3-ethoxycarbonylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   2-(3-aminobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylic    acid,-   5-methyl-2-(3-nitrobenzyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-benzyl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-5-methyl-4-oxo-2-(thiophen-2-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-5-methyl-4-oxo-2-(thiophen-3-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(5-chlorothiophen-2-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(2-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(3-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(4-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(2-chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(3-chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(4-chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(3-bromobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-5-methyl-2-(3-methylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-5-methyl-4-oxo-2-(2-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-5-methyl-4-oxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(cyclopenten-1-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,-   3-amino-2-(cyclohexen-1-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic    acid,    and the like.

The compounds of the formula (I) of this invention can also form salts,for example, alkali metal salts such as sodium salts, potassium salts,lithium salts and the like; alkaline earth metal salts such as calciumsalts, magnesium salts and the like; salts with organobases such astriethylamine, dicyclohexylamine, pyrrolidine, morpholine, pyridine andthe like; and ammonium salts. Depending on the kind(s) ofsubstituent(s), they can also form salts with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like; or organic acids such as acetic acid,oxalic acid, citric acid, lactic acid, tartaric acid, p-toluenesulfonicacid and the like. Of these salts, particularly pharmaceuticallyacceptable salts are preferred.

According to the present invention, the compounds of the formula (I) inwhich Z stands for O can be prepared, for example, by either one of themethods (a)-(c) as described in the following, depending on the kind ofR². Furthermore, the compounds of the formula (I) in which Z stands forO and R² and R³ together form tetramethylene group can be prepared, forexample, by the method (d) as described in the following. The compoundsof the formula (I) in which Z stands for S can be prepared, for example,by the method (e) as described in the following.

Method (a): A compound of the formula (I) in which Z stands for O and R²stands for hydrogen, i.e., a thienopyrimidine derivative represented bythe formula,

in the formula,

R¹, R³ and n have the previously defined significations, can be preparedby, for example, reacting a thiophene derivative of the formula,

in the formula,

R¹ and n have the previously defined significations, and

R and R′ stand for, independently of each other, C₁₋₆ alkyl, with anitrile compound represented by the formula,R³—CN  (III)in the formula,

R³ has the previously given signification, to form a compoundrepresented by the following formula,

in the formula,

R¹, R³, n and R have the previously defined significations, andsuccessively hydrolyzing the ester in 6-substituent on thethienopyrimidine ring in the compound of above formula (IV).

Method (b): A compound of the formula (I) in which Z stands for O and R²stands for C₁₋₆ alkyl or phenylC₁₋₆ alkyl, i.e., 3-alkylthienopyrimidinederivative represented by the formula,

in the formula,

R¹, R³ and n have the previously defined significations, and

R²¹ stands for C₁₋₆ alkyl or phenylC₁₋₆ alkyl,

can be prepared by N-alkylating 3-nitrogen atom on the pyrimidine ringin a compound of above formula (IV) obtainable by the method (a),followed by ester hydrolysis similar to that in the method (a). When thecompound of the formula (IV) has other substituent(s) liable toparticipate in the N-alkylation, for example, carboxyl, hydroxyl, aminoother than the 3-nitrogen atom on the pyrimidine ring, it isadvantageous to protect such group(s) with adequate protective group(s)in advance of the N-alkylation of 3-nitrogen atom on the pyrimidine ringand removing the protective group(s) after the end of the reaction.Method (c): A compound of the formula (I) in which Z stands for O and R²stands for amino, i.e., 3-aminothienopyrimidine derivative of theformula,

in the formula,

R¹, R³ and n have the previously defined significations, can beprepared, for example, by subjecting a compound of the formula,

in the formula,

R¹, R³, n, R and R′ have the previously defined significations, to ringclosure reaction with hydrazine, and thereafter hydrolyzing the estersimilarly to the method (a).

Method (d): A compound of the formula (I) in which Z stands for O and R²and R³ together form tetramethylene, i.e., a compound of the followingformula,

in the formula,

R¹ and n have the previously defined significations, can be prepared,for example, by reacting a compound of the formula (II) with a compoundof the formula,

in the formula,

Hal stands for halogen,

and subjecting the resulting compound of the formula,

in the formula,

-   -   R¹, n, R and Hal have the previously defined significations, to        ring closure reaction, to lead it to a compound of the following        formula,

in the formula,

R¹, n and R have the previously defined significations, and thereafterhydrolyzing the ester similarly to the method (a).

Method (e): A compound of the formula (I) in which Z stands for S, i.e.,a thienopyrimidine derivative of the following formula,

in the formula,

R¹, R², R³ and n have the previously defined significations, can beprepared by treating a compound of the following formula,

in the formula,

R¹, R², R³, n and R have the previously defined significations, withLawesson's reagent to lead it to a compound of the following formula,

in the formula,

R¹, R², R³, n and R have the previously defined significations, andthereafter hydrolyzing the ester similarly to the method (a).

The reaction of a compound of the formula (II) with a nitrile compoundof the formula (III) in the above method (a) can be performed generallyin an inert solvent such as amides including N,N-dimethylformamide andN,N-dimethylacetamide; alcohols including methanol, ethanol andisopropanol; or ethers including tetrahydrofuran and dioxane, in thepresence of an acid catalyst such as hydrochloric acid, hydrobromic acidand p-toluenesulfonic acid, at −20° C. to the refluxing temperature ofthe reaction mixture, preferably 0-50° C.

The use ratio of the nitrile compound of the formula (III) to thecompound of the formula (II) is not particularly limited, while it ispreferable to use generally at least 1 mol, in particular, within arange of 1.05-5 mols, inter alia, 1.2-2 mols, of the nitrile compound ofthe formula (III), per mol of the compound of the formula (II). The acidcatalyst can be used within a range of about 0.2-about 50 mols, per molof the compound of the formula (II).

The hydrolysis of the ester at the 6-substituent on thionopyrimidinering in the resulting compound of the formula (IV) can follow any methodheretofore known per se, for example, by suspending or dissolving thecompound of the formula (IV) in a mixed solvent of alcohol such asmethanol, ethanol or the like with water, at temperatures within a rangeof 0° C.—refluxing temperature of the reaction mixture, preferably fromroom temperature to refluxing temperature of the reaction mixture, inthe presence of alkali such as sodium hydroxide, potassium hydroxide,potassium carbonate or the like. The use ratio of the alkali to thecompound of the formula (IV) is not critical, but the alkali can begenerally used within a range of about 1-20 mols per mol of the compoundof the formula (IV).

The N-alkylation reaction of the compound of the formula (IV) in theabove method (b) can be performed, for example, by nucleophilicsubstitution reaction using alkyl halide (R²¹-Hal, wherein R²¹ and Halhave the previously defined significations). The reaction is generallyconducted in an inert organic solvent such as amides includingN,N-dimethylformamide and N,N-dimethylacetamide; alcohols includingmethanol, ethanol and isopropanol, ethers such as tetrahydrofuran anddioxane; organic bases including pyridine; acetonitrile, or the like, inthe optional presence of alkali such as sodium hydride, sodiummethoxide, potassium butoxide, potassium hydroxide, potassium carbonateor the like; or organic base such as triethylamine,2,6-di-tert-butyl-4-methylpyridine or the like, at temperatures ranging0° C. to refluxing temperature of the reaction mixture, preferably roomtemperature to refluxing temperature of the reaction mixture.

The use ratio of alkyl halide used for N-alkylation of the compound ofthe formula (IV), to the same compound is not critical, while it isgenerally at least 1 mol, preferably 1.1-20 mols, inter alia, 1.2-10mols, per mol of the compound of the formula (IV). Also the alkali ororganic base can be normally used within a range of 1.1-about 20 molsper mol of the compound of the formula (IV).

The ring closure reaction of the compound of the formula (V) withhydrazine in the method (c) can be generally performed in an inertorganic solvent such as amides including N,N-dimethylformamide andN,N-dimethylacetamide; alcohols including methanol, ethanol andisopropanol; ethers including tetrahydrofuran and dioxane; attemperatures within a range of 0° C. to the refluxing temperature of thereaction mixture, preferably room temperature to the refluxingtemperature of the reaction mixture.

The use ratio of hydrazine to the compound of the formula (V) is notcritical, while hydrazine can be used within a range of at least 1 mol,preferably 1.2-10 mols, inter alia, 1.3-5 mols, per mol of the compoundof the formula (V).

The reaction of a compound of the formula (II) with a halogenatednitrile compound of the formula (VI) in the method (d) can be performedby a method similar to the reaction of a compound of the formula (II)with a nitrile compound of the formula (III) in the method (a).

The ring closure reaction of the compound of the formula (VII) in themethod (d) can be performed by a method similar to the N-alkylation ofthe compound of the formula (IV) in the method (b).

The treating reaction of the compound of the formula (IX) withLawesson's reagent in the method (e) can be performed generally in aninert organic solvent, for example, ethers including tetrahydrofuran anddioxane; or aromatic hydrocarbons including benzene and toluene; attemperatures ranging from 0° C. to the refluxing temperature of thereaction mixture, preferably room temperature to the refluxingtemperature of the reaction mixture.

The use ratio of Lawesson's reagent to the compound of the formula (IX)is not particularly limited, while generally it can be at least 0.5 mol,preferably 0.5-5 mols, inter alia, 0.6-2 mols, per mol of the compoundof the formula (IX).

Most of the thiophene derivatives of the formula (II) which are used asstarting materials in the reactions of above methods (a) and (d) arenovel compounds never disclosed in known literature, but they can bereadily synthesized by methods similar to those for syntheses of knownthiophene derivatives, for example, following the route as shown in thefollowing reaction scheme 1. For the particulars such as the reactionconditions, refer to later appearing Production Example 1.

in the above formulae, R¹, n, R and R′ have the previously definedsignifications.

Also nearly all of the nitrile compounds of the formula (III) which areused as the starting materials in the reaction of above method (a) areknown. Even those unknown can be readily synthesized following knownmethods of synthesis, for example, following the methods disclosed inReferential Literature, SYNTHESIS, 1980, 150-151 or Bioorg. Med. Chem.Lett., 2002 (12) 1275-1278.

Furthermore, the compounds of the formula (V) which are used as thestarting materials in the method (c) can be synthesized, for example, byamidation of the compounds of the formula (II) with carboxylic acidcompounds of the formula,R³—COOH  (IX)

in which R³ has the previously defined signification, or reactivederivatives thereof (e.g., acid halide, acid anhydride, mixed acidanhydride, active amide, active ester and the like).

Those compounds of the formula (I) of the present invention produced inthe reaction mixtures of above-described methods (a)-(d) can be isolatedfrom the reaction mixtures and purified by the means known per se, forexample, recrystallization, column chromatography, thin layerchromatography and the like.

Those thienopyrimidine derivatives represented by the formula (I) orsalts thereof provided by the present invention and also Compound A andsalts thereof exhibit potent PDE9-inhibiting activity, and are usefulfor curative and treating agents of diseases associated with degradationof cGMP by PDE9, for example, overactive bladder syndrome, pollakiuria,urinary incontinence,

dysuria in benign prostatic hyperplasia, neurogenic bladder,interstitial cystitis, urolithiasis, benign prostatic hyperplasia,erectile dysfunction, cognitive impairment, neuropathy, Alzheimer'sdisease, pulmonary hypertension, chronic obstructive pulmonary disease,ischemic heart disease, hypertension, angina, myocardial infarction,arteriosclerosis, thrombosis, embolism, type 1 diabetes, and type 2diabetes.

Among the thienopyrimidine derivatives represented by the formula (I)and salts thereof that are provided by the present invention andCompound A and salts thereof, those which exhibit slight PDE5-inhibitingactivity in addition to their PDE9-inhibiting activity are expected toachieve also the functional effects based on the PDE5-inhibitingactivity.

PDE9-inhibiting activity, PDE5-inhibiting activity and improving actionon pathological models of dysuria exhibited by the compounds of theformula (I), Compound A and their salts are demonstrated by thefollowing experiments.

(1) Measurement of PDE9-Inhibiting Activity:

1) Preparation of Human Recombinant PDE9 Protein

Based on the base sequence of hsPDE9A1 registered with GenBank database(accession No.: AF048837), hsPDE9A1 fragment was amplified by polymerasechain reaction under the following conditions, using the followingsequence (Amasham Pharmacia Biotech) as the primer and Human ProstateMATCHMAKER cDNA library (CLONTECH) as the template DNA, with Pfu TurboDNA polymerase (STRATAGENE):

hPDE9-5A primer: [SEQ ID NO: 1] CTAGCTAGCCACCATGGGATCCGGCTCCTCChPDE9-3A primer: [SEQ ID NO: 2]TTTTCCTTTTGCGGCCGCTTATTAGGCACAGTCTCCTTCACTG

PCR condition: [95° C., 5 min]×1 cycle, [(95° C., 1 min), (58° C., 2min), (72° C., 3 min)]×25 cycle, [72° C., 10 min]×1 cycle

Thus obtained hsPDE9A1 fragment was given a restricted enzymatictreatment with NheI and NotI, and thereafter inserted into pcDNA 3.1(+)expression vector (Invitrogen) to let it serve as a human PDE9expression vector.

Human PDE9 expression vector-transformed Escherichia coli was massincubated to produce a large amount of PDE9 expression vector, which wastransiently transfected into COS-1 cells, with LIPOFECTAMINE 2000Reagent (GIBCO). The cells were homogenized in ice-cooled buffer A (40mmol/L Tris-HCl, pH7.5, 15 mmol/L benzamidine; 15 mmol/L2-mercaptoethanol; 1 μg/mL Pepstatin A, 1 μg/mL Leupeptin, 5 mmol/LEDTA) and centrifuged at 4° C., 14,000×g for 10 minutes. The supernatantwas isolated to provide human recombinant PDE9 protein solution.

2) Measurement of PDE9-Inhibiting Activity

To 150 μL of buffer B (70 mmol/L Tris-HCl, pH7.5; 16.7 mmol/L MgCl₂,33.3 nmol/L [³H]-cGMP) solution containing [³H]-cGMP (specificactivity=244.2 GBq/mmol) at a concentration of 33.3 nmol/L, 50 μL of asolution of the compound to be evaluated (formed by dissolving thecompound in DMSO and diluting it with distilled water to DMSOconcentration of 5%) and 50 μL of the PDE9 protein solution as preparedin the above, as diluted with buffer C (40 mmol/L Tris-HCl, pH7.5, 15mmol/L benzamidine, 15 mmol/L 2-mercaptoethanol, 1 μg/mL Pepstatin A, 1μg/mL Leupeptin) by 1,500×, were added under cooling with ice. Thismixed solution was incubated at 30° C. for 30 minutes and the enzymaticreaction of PDE9 was terminated by heating the system in boiling waterfor 90 seconds. Returning the system to room temperature, 50 μL of Snakevenom (SIGMA: 1 mg/mL) was added, followed by 10 minutes' incubation at30° C., to convert the [³H]-5′-GMP produced in the previous reaction to[³H]-guanosine. This reaction solution was passed through a columnfilled with 1 mL of 0.5 mol/L hydrochloric acid-activatedcation-exchange resin (Bio-Rad AG50W-X4 resin, mesh size 200-400) andremoved of the unreacted substrate ([³H]-cGMP) by elution with 12 mL ofdistilled water. Thereafter [³H]-guanosine was eluted with 3 mL of 3mol/L aqueous ammonia and its radiation activity was measured withliquid scintillation counter.

PDE9 inhibition of the tested compound can be calculated by thefollowing formula:

$\left\lbrack \left( {1 - \frac{{radiation}\mspace{14mu}{activity}\mspace{14mu}{where}\mspace{14mu}{test}\mspace{14mu}{compound}\mspace{14mu}{is}\mspace{14mu}{used}}{{radiation}\mspace{14mu}{activity}\mspace{14mu}{in}\mspace{14mu}{control}\mspace{14mu}{test}}} \right) \right\rbrack \times 100$

From the inhibition ratios at various concentration levels of eachtested compound, its IC₅₀ value against PDE9 was determined. The resultsare shown in Table A given later.

(2) Measurement of PDE5-Inhibiting Activity:

1) Preparation of Human Recombinant PDE5 Protein

Based on the base sequence of hsPDE5A1 registered with GenBank database(accession No.: NM_(—)001083), hsPDE5A1 fragment was amplified bypolymerase chain reaction under the following conditions, using thefollowing sequence (SIGMA GENOSYS) as the primer and Human ProstateMATCHMAKER cDNA library (CLONTECH) as the template DNA, with KDD plusDNA polymerase (TOYOBO):

hPDE5-5′ E primer: [SEQ ID NO: 3] CGGAATTCCAACCATGGAGCGGGC hPDE5-3′primer: [SEQ ID NO: 4] GCTCTAGATCAGTTCCGCTTGGCCTGG

PCR condition: [94° C., 2 min]×1 cycle, [(94° C., 30 sec), (65° C., 30sec), (68° C. 3 min)]×25 cycle, [68° C., 6 min]×1 cycle

Thus obtained hsPDE5A1 fragment was given a restricted enzymatictreatment with XBaI and EcoRI, and thereafter inserted into pcDNA 3.1(+)expression vector (Invitrogen) to let it serve as a human PDE5expression vector.

Human PDE5 expression vector-transformed Escherichia coli was massincubated to produce a large amount of PDE5 expression vector, which wastransiently transfected into COS-1 cells, with LIPOFECTAMINE 2000Reagent (GIBCO). The cells were homogenized in ice-cooled buffer A andcentrifuged at 4° C., 14,000×g for 10 minutes. The supernatant wasisolated to provide human recombinant PDE5 protein solution.

2) Measurement of PDE5-Inhibiting Activity

By a method similar to the measurement of PDE9-inhibiting activity,PDE5-inhibiting activity of the test compounds was measured, theirinhibition was calculated and IC₅₀ value to PDE5 of each of thecompounds was determined. The results are shown in the following TableA, concurrently with the compounds' IC₅₀ values against PDE9.

TABLE A Inhibitory Activity (IC₅₀ value: nmol/L) Compound StructuralFormula PDE9 PDE5 Example 1

22 17,784 Example 2

40 21,116 Example 3

34 6,897 Example 10

30 6,767 Example 12

24 4,430 Example 22

34 22,159 Example 36

38 915 Example 40

46 20,008 Example 49

44 18,903 Example 52

38 3,417 Example 53

22 5,712 Example 57

42 19,834 Example 65

28 8,591 Example 66

54 1,638 Example 101

14 34,879 Example 102

15 41,232 Example 103

19 34,389 Example 104

10 15,819 Example 105

15 30,222 Example 106

9 2,282 Example 107

22 12,065 Example 108

9 1,636 Example 109

31 1,541 Example 110

13 642 Example 111

11 712 Example 112

5 1,112 Example 113

6 3,507 Example 114

4 73 Example 115

7 495 Example 116

48 70 Example 117

24 843 Example 118

11 8,874 Example 119

5 721 Compound A

35 10,045(3) Investigation of PDE9 Inhibitory Activity on Dysuria PathologicalModel

Three to four weeks old female Hartley strain guinea pigs (Nippon SLC)were laparotomized under anesthesia with pentobarbital (30 mg/kg i.p.),and a polyethylene tube of 1.4 mm in width and 2.0 mm in inner diameterwas placed in each guinea pig's urethra to the distal side by 1-2 mmfrom the bladder neck. After closing the incision, the guinea pigs werereared for at least 3 weeks to provide a model of urethral obstructionwith the guinea pigs in which rise in intravesical pressure notaccompanied by voiding (non-voiding contraction) and residual urine wereinduced.

The model was catheterized under anesthesia with urethane (1 g/kg i.p.)at the apex of urinary bladder and right jugular vein forcystometrography and intravenous administration, respectively. The otherend of the bladder catheter was connected to a pressure transducer andinfusion pump through three way stopcock. By means of the infusion pump,physiological saline was continuously infused into the bladder at a rateof 0.4 mL/min to induce micturition reflex. Immediately after themicturition reflex was induced, the physiological saline infusion intothe bladder was stopped. The intravesical pressure at the time themicturition occurred was measured with the pressure transducer and thecystometrogram was recorded with pen recorder. The urine voided wascollected with a disposable type weighing dish to measure its weight.Further the physiological saline remained in the bladder was sucked withsyringe through the bladder catheter to measure the residual urinevolume. Multiple operation cycles (normally 4 times) of suspendingphysiological saline infusion when micturition reflex was induced andresuming the infusion after about 1 minute to induce next micturitionreflex, were repeated to stabilize the voiding response.

Thereafter either the compound solutions (solution of the compound indistilled water at a concentration of 3 mg/mL was diluted withphysiological saline to 1, 0.3 or 0.1 mg/mL) or physiological saline, ofa volume 10 mL/kg, was intravenously administered to the model over 4minutes, during which the above cyclic operations were repeated from theinitiation of the administration to 30 minutes after the administration,to measure the intravesical pressure, voided urine volume and residualurine volume. Also the frequency of non-voiding contraction occurredduring the operations was measured. The respective mean values offrequency of non-voiding contraction and residual urine volume in theexperiment using several guinea pigs are shown in the following Table B.

TABLE B Frequency of non-voiding contraction (count/min) Residual urinevolume (mL) pre- post- quanti- pre- post- quanti- Dose adminis- adminis-tative adminis- adminis- tative Compound (i.v., mg/kg) tration tratonchange tration traton change Physiological — 1.10 1.08 −0.02 1.44 1.43−0.01 saline Example 2 1 0.91 0.47 −0.44 1.27 1.23 −0.04 10 0.91 0.78−0.13 1.27 1.02 −0.25 Example 10 0.3 1.16 0.80 −0.36 0.95 1.08 +0.13 31.16 0.49 −0.67 0.95 1.11 +0.16 10 1.16 0.60 −0.56 0.95 0.95 0.00Example 36 1 0.96 0.79 −0.17 0.82 0.86 +0.04 3 1.16 0.77 −0.39 1.33 1.03−0.30 10 1.11 0.64 −0.47 1.06 0.64 −0.42 Example 104 0.3 1.08 0.55 −0.531.54 1.02 −0.52 3 1.44 0.78 −0.66 1.37 0.88 −0.49 10 1.57 0.83 −0.741.68 0.62 −1.06 Example 112 0.3 1.12 1.02 −0.10 1.02 0.91 −0.11 3 1.120.76 −0.36 1.02 0.27 −0.75 10 1.12 0.59 −0.53 1.02 0.48 −0.54

As shown in above Table B, compounds of the present invention alsoexhibit significant residual urine-reducing action.

Thus the thienopyrimidine derivatives represented by the formula (I) ofthe present invention and Compound A, or their salts can be administeredas PDE9 inhibitor or PDE9 inhibitor concurrently exhibiting slight PDE5inhibitory activity, for therapy or treatment of PDE9-associateddiseases of human and other mammals, orally or parenterally (e.g.,intramuscular injection, intravenous injection, rectal administration,percutaneous administration and the like).

The drugs of the present invention can be formulated, together withnon-toxic excipients, any preparation forms such as solid (e.g., tablet,hard capsule, soft capsule, granule, powder, fine granule, pill, trocheand the like); semi-solid (e.g., suppository, ointment and the like); orliquid (e.g., injection, emulsion, suspension, lotion, spray and thelike). As non-toxic excipients useful for such formulation, for example,starch, gelatin, glucose, lactose, fructose, maltose, magnesiumcarbonate, talc, magnesium stearate, methyl cellulose, carboxymethylcellulose or salts thereof, gum Arabic, polyethylene glycol,p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol,vaseline, Carbowax, glycerine, sodium chloride, sodium sulfite, sodiumphosphate, citric acid and the like can be named. These formulations mayalso contain other therapeutically useful drugs.

Content of a compound of the formula (IA) in these formulations differsdepending on the preparation form and administration route, whilegenerally it can be present at a concentration of 0.1-50 wt % in solidand semi-solid forms, and of 0.05-10 wt %, in liquid form.

Dosage of a compound of the formula (IA) is variable over a broad rangeaccording to the kind of warm-blooded animals including human to betreated, kind of involved disease, administration route, seriousness ofsymptoms, doctor's diagnosis and the like. Whereas, generally it can bewithin a range of 0.01-5 mg/kg per day, preferably 0.02-2 mg/kg per day,it being obviously possible to administer doses less than the abovelower limit or more than the above upper limit, for example, accordingto individual patient's symptom and doctor's diagnosis. The dosage canbe administered once a day or dividedly plural times per day.

EXAMPLES

Hereinafter the present invention is explained in further details,referring to Examples, Production Examples and Formulation Examples, itbeing understood that the invention is not limited to those Examples.

Production Example 1 Ethyl5-methyl-4-oxo-2-(thiophen-3-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

515 Milligrams of diethyl 5-amino-3-methylthiophene-2,4-dicarboxylateand 296 mg of 3-thiopheneacetonitrile were added to 8 mL of 4N hydrogenchloride-dioxane solution and stirred for 10 hours. Thereafter theliquid reaction mixture was poured on ice, and its pH was adjusted to8-9 with 25% aqueous ammonia. Whereupon precipitated crystals wererecovered by filtration and washed first with water, and then withhexane. The crude crystals were recrystallized from a liquid mixture ofN,N-dimethylformamide and cyclohexane, to provide 397 mg of the titlecompound.

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 2.81 (3H, s), 3.97 (2H, s),4.30 (2H, q, J=7.1 Hz), 7.0-7.6 (3H, m), 12.74 (1H, br s)

MS (m/z): 334 (M⁺)

Compounds of Production Examples 2-20 were prepared in the mannersimilar to the Production Example 1.

Production Example 2 Ethyl5-methyl-4-oxo-2-(thiophen-2-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 2.81 (3H, s), 4.17 (2H, s),4.30 (2H, q, J=7.1 Hz), 6.9-7.5 (3H, m), 12.80 (1H, br s)

MS (m/z): 334 (M⁺)

Production Example 3 Ethyl2-(5-chlorothiopen-2-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=6.9 Hz), 2.81 (3H, s), 4.14 (2H, s),4.30 (2H, q, J=7.1 Hz), 6.91 (1H, d, J=3.9 Hz), 6.98 (1H, d, J=3.9 Hz),12.79 (1H, br s)

MS (m/z): 370 (M⁺+2), 368 (M⁺)

Production Example 4 Ethyl5-methyl-2-(4-methylthiazol-2-ylmethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 2.32 (3H, d, J=0.8 Hz), 2.82(3H, s), 4.30 (2H, q, J=7.1 Hz), 4.37 (2H, s), 7.21 (1H, d, J=0.8 Hz),12.85 (1H, br s)

MS (m/z): 349 (M⁺)

Production Example 5 Ethyl2-(2-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.1 Hz), 2.82 (3H, s), 4.05 (2H, s),4.29 (2H, q, J=7.2 Hz), 7.1-7.5 (4H, m), 12.80 (1H, br s)

MS (m/z): 346 (M⁺)

Production Example 6 Ethyl2-(3-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 2.81 (3H, s), 3.99 (2H, s),4.29 (2H, q, J=7.1 Hz), 7.0-7.5 (4H, m), 12.77 (1H, br s)

MS (m/z): 346 (M⁺)

Production Example 7 Ethyl2-(3-chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 2.81 (3H, s), 3.98 (2H, s),4.29 (2H, q, J=7.1 Hz), 7.2-7.4 (3H, m), 7.45 (1H, s), 12.77 (1H, br s)

MS (m/z): 364 (M⁺+2), 362 (M⁺)

Production Example 8 Ethyl2-(2,3-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=6.9 Hz), 2.83 (3H, s), 4.21 (2H, s),4.29 (2H, q, J=7.2 Hz), 7.3-7.7 (3H, m), 12.81 (1H, br s)

MS (m/z): 398 (M⁺+2), 396 (M⁺)

Production Example 9 Ethyl2-(2,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.1 Hz), 2.82 (3H, s), 4.14 (2H, s),4.29 (2H, q, J=7.2 Hz), 7.3-7.7 (3H, m), 12.82 (1H, br s)

MS (m/z): 398 (M⁺+2), 396 (M⁺)

Production Example 10 Ethyl2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.0 Hz), 2.81 (3H, s), 4.00 (2H, s),4.29 (2H, q, J=7.2 Hz), 7.3-7.7 (3H, m), 12.77 (1H, br s)

MS (m/z): 398 (M⁺+2), 396 (M⁺)

Production Example 11 Ethyl2-(3-bromobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=6.9 Hz), 2.81 (3H, s), 3.98 (2H, s),4.29 (2H, q, J=7.1 Hz), 7.2-7.7 (4H, m), 12.76 (1H, br s)

MS (m/z): 408 (M⁺+2), 406 (M⁺)

Production Example 12 Ethyl2-(4-bromobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 2.80 (3H, s), 3.95 (2H, s),4.29 (2H, q, J=7.1 Hz), 7.2-7.6 (4H, m), 12.76 (1H, br s)

MS (m/z): 408 (M⁺+2), 406 (M⁺)

Production Example 13 Ethyl5-methyl-2-(3-methylbenzyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 2.28 (3H, s), 2.80 (3H, s),3.91 (2H, s), 4.29 (2H, q, J=7.1 Hz), 7.0-7.3 (4H, m), 12.75 (1H, br s)

MS (m/z): 342 (M⁺)

Production Example 14 Ethyl5-methyl-2-(4-methylbenzyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=6.9 Hz), 2.26 (3H, s), 2.80 (3H, s),3.90 (2H, s), 4.29 (2H, q, J=7.2 Hz), 7.13, 7.23 (4H, AB, J=7.7 Hz),12.74 (1H, br s)

MS (m/z): 342 (M⁺)

Production Example 15 Ethyl5-methyl-4-oxo-2-(2-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, t, J=6.9 Hz), 2.82 (3H, s), 4.24 (2H, s),4.28 (2H, q, J=7.2 Hz), 7.4-7.8 (4H, m), 12.83 (1H, br s)

MS (m/z): 396 (M⁺)

Production Example 16 Ethyl5-methyl-4-oxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=6.9 Hz), 2.81 (3H, s), 4.09 (2H, s),4.29 (2H, q, J=7.2 Hz), 7.5-7.7 (3H, m), 7.76 (1H, s), 12.80 (1H, br s)

MS (m/z): 396 (M⁺)

Production Example 17 Ethyl5-methyl-4-oxo-2-(4-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.1 Hz), 2.81 (3H, s), 4.08 (2H, s),4.29 (2H, q, J=7.1 Hz), 7.58, 7.70 (4H, AB, J=8.1 Hz), 12.82 (1H, br s)

MS (m/z): 396 (M⁺)

Production Example 18 Ethyl2-(cyclopent-1-enylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 1.7-1.9 (2H, m), 2.2-2.4(4H, m), 2.81 (3H, s), 3.41 (2H, s), 4.30 (2H, q, J=7.2 Hz), 5.47 (1H,d, J=1.5 Hz), 12.56 (1H, br s)

MS (m/z): 318 (M⁺)

Production Example 19 Ethyl2-cyclopentylmethyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.1-1.3 (2H, m), 1.30 (3H, t, J=7.1 Hz), 1.4-1.9(6H, m), 2.2-2.4 (1H, m), 2.61 (2H, d, J=7.3 Hz), 2.81 (3H, s), 4.29(2H, q, J=7.1 Hz), 12.50 (1H, br s)

MS (m/z): 320 (M⁺)

Production Example 20 Ethyl2-cyclohexylmethyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 0.9-1.3 (5H, m), 1.31 (3H, t, J=7.1 Hz), 1.5-1.9(6H, m), 2.81 (3H, s), 4.30 (2H, q, J=7.1 Hz), 12.48 (1H, br s)

MS (m/z): 334 (M⁺)

Production Example 21 Ethyl2-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

A mixture of 1.15 g of ethyl2-chloromethyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate,745 mg of tert-butoxycarbonylpiperazine, 20 mL of ethylene glycol and400 mg of triethylamine was stirred at 80° C. for 3 hours. Thereafterwater was added to the reaction mixture, followed by extraction withchloroform, drying over anhydrous magnesium sulfate, and removal of thesolvent by distillation under reduced pressure. The residue was purifiedon silica gel column chromatography (ethylacetate:chloroform:hexane=2:1:1) to provide 1.36 g (78%) of the titlecompound.

¹H-NMR (CDCl₃) δ: 1.40 (3H, t, J=7.0 Hz), 1.47 (9H, s), 2.55 (4H, t,J=4.8 Hz), 2.94 (3H, s), 3.51 (4H, t, J=4.8 Hz), 3.58 (2H, s), 4.37 (2H,q, J=7.3 Hz)

MS (m/z): 436 (M⁺), 129 (base)

Production Example 22 Ethyl3-benzyl-2,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylate

A mixture of 252 mg of ethyl2,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate, 138mg of potassium carbonate, 15 mL of acetonitrile and 1 mL of benzylchloride was heated under reflux overnight. After condensing thereaction mixture under reduced pressure, the residue was purified onsilica gel column chromatography (chloroform:methanol=100:1) to provide153 mg (45%) of the title compound.

¹H-NMR (CDCl₃) δ: 1.40 (3H, t, J=6.9 Hz), 2.54 (3H, s), 2.96 (3H, s),4.37 (2H, q, J=6.9 Hz), 5.35 (2H, s), 7.1-7.2 (2H, m), 7.2-7.4 (3H, m)

MS (m/z): 342 (M⁺), 91 (base)

Production Example 23 Ethyl2-(3,4-dichlorobenzyl)-3,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

A mixture of 100 mg of ethyl2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate,40 mg of potassium carbonate, 10 mL of acetonitrile and 40 mg of methyliodide was heated under reflux for 1.5 hours. After condensing thereaction mixture under reduced pressure, the residue was purified onsilica gel column chromatography (ethyl acetate:hexane=1:1) to provide60 mg (58%) of the title compound.

¹H-NMR (CDCl₃) δ: 2.92 (3H, s), 3.47 (3H, s), 3.88 (3H, t, J=6.9 Hz),4.15 (2H, s), 4.37 (2H, q, J=6.9 Hz), 7.0-7.1 (1H, m), 7.34 (1H, d,J=1.9 Hz), 7.41 (1H, d, J=8.4 Hz)

MS (m/z): 412 (M⁺+2), 410 (M⁺), 159 (base)

Production Example 24 Butyl5-amino-4-ethoxycarbonyl-3-methyl-2-thiopheneacetate

A mixture of 1.72 g of butyl 4-oxopentanoate, 352 mg of sulfur, 1.13 gof ethyl cyanoacetate, 5 mL of ethanol and 1 mL of diethylamine wasstirred at room temperature overnight. Chloroform was added to thereaction mixture, followed by washing with saturated aqueous sodiumbicarbonate solution, drying over anhydrous magnesium sulfate andremoval of the solvent by distillation under reduced pressure. Theresidue was purified on silica gel column chromatography (hexane:ethylacetate=3:1) to provide 1.20 g (40.1%) of the title compound.

¹H-NMR (CDCl₃) δ: 0.9-1.0 (3H, m), 1.3-1.5 (5H, m), 1.5-1.7 (2H, m),2.19 (3H, s), 2.5-2.6 (2H, m), 2.7-2.8 (2H, m), 4.0-4.2 (2H, m)

MS (m/z): 299 (M⁺), 198 (base)

Production Example 25 Butyl2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-acetate

A mixture of 900 mg of butyl5-amino-4-ethoxycarbonyl-3-methyl-2-thiopheneacetate, 558 mg of(3,4-dichlorophenyl)acetonitrile and 20 mL of 4N hydrochloricacid/1,4-dioxane solution was stirred at room temperature overnight. Icewater was added to the reaction mixture, followed by neutralization with25% aqueous ammonia, extraction with chloroform, drying over anhydrousmagnesium sulfate and removal of the solvent by distillation underreduced pressure. The residue was purified on silica gel columnchromatography (chloroform:methanol=50:1) to provide 500 mg (38%) of thetitle compound.

¹H-NMR (CDCl₃) δ: 0.8-1.0 (3H, m), 1.3-1.5 (2H, m), 1.6-1.7 (2H, m),2.58 (3H, s), 3.81 (2H, s), 4.01 (2H, s), 4.1-4.2 (2H, m), 7.2-7.4 (1H,m), 7.39 (1H, d, J=8.5 Hz), 7.59 (1H, d, J=2.3 Hz), 12.35 (1H, s)

MS (m/z): 440 (M⁺+2), 438 (M⁺)

Production Example 26 Ethyl5-amino-4-ethoxycarbonyl-3-methyl-2-thiophenepropionate

The title compound was obtained in the manner similar to ProductionExample 24.

MS (m/z): 285 (M⁺)

Production Example 27 Ethyl2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydro-6-thieno[2,3-d]pyrimidine-6-propionate

The title compound was obtained in the manner similar to ProductionExample 25.

¹H-NMR (DMSO-d₆) δ: 1.16 (3H, t, J=7.1 Hz), 2.39 (3H, s), 2.59 (2H, t,J=7.1 Hz), 3.00 (2H, t, J=7.1 Hz), 3.94 (2H, s), 4.05 (2H, q, J=7.1 Hz),7.2-7.7 (3H, m), 12.43 (1H, br s)

MS (m/z): 426 (M⁺+2), 424 (M⁺)

Production Example 28 Ethyl5-amino-4-ethoxycarbonyl-3-methyl-2-thiophenebutyrate

The title compound was obtained in the manner similar to ProductionExample 24.

¹H-NMR (CDCl₃) δ: 1.1-1.4 (6H, m), 1.7-1.9 (2H, m), 2.17 (3H, s),2.2-2.4 (2H, m), 2.60 (2H, t, J=7.5 Hz), 4.0-4.2 (2H, m), 4.2-4.4 (2H,m), 5.91 (2H, br s)

MS (m/z): 299 (M⁺)

Production Example 29 Ethyl2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-butyrate

The title compound was obtained in the manner similar to ProductionExample 25.

¹H-NMR (DMSO-d₆) δ: 1.17 (3H, t, J=7.1 Hz), 1.7-1.9 (2H, m), 2.34 (2H,t, J=7.3 Hz), 2.37 (3H, s), 2.76 (2H, t, J=7.5 Hz), 3.94 (2H, s), 4.04(2H, q, J=7.1 Hz), 7.2-7.7 (3H, m), 12.44 (1H, br s)

MS (m/z): 440 (M⁺+2), 438 (M⁺)

Production Example 30 Diethyl5-amino-3-trifluoromethylthiophene-2,4-dicarboxylate

The title compound was obtained in the manner similar to ProductionExample 24.

MS (m/z): 311 (M⁺)

Production Example 31 Ethyl2-(3,4-dichlorobenzyl)-4-oxo-5-trifluoromethyl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 25.

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.1 Hz), 4.04 (2H, s), 4.36 (2H, q,J=7.1 Hz), 7.3-7.7 (3H, m), 13.05 (1H, br s)

MS (m/z): 452 (M⁺+2), 450 (M⁺)

Production Example 32 4-Ethyl-2-methyl5-amino-3-methoxymethylthiophene-2,4-dicarboxylate

The title compound was obtained in the manner similar to ProductionExample 24.

MS (m/z): 273 (M⁺)

Production Example 33 Methyl2-(3,4-dichlorobenzyl)-5-methoxymethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 25.

¹H-NMR (DMSO-d₆) δ: 3.58 (3H, s), 3.79 (2H, s), 3.90 (3H, s), 3.94 (2H,s), 7.2-7.7 (3H, m), 12.48 (1H, br s)

MS (m/z): 414 (M⁺+2), 412 (M⁺)

Compounds of Production Examples 34-79 were synthesized in the mannersimilar to Production Example 1.

Production Example 34 Ethyl5-methyl-2-(2-naphthyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

MS (m/z): 364 (M⁺, base)

Production Example 35 Ethyl2-(2-methoxycarbonylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, t, J=7.1 Hz), 2.82 (3H, s), 3.72 (3H, s),4.28 (2H, q, J=7.1 Hz), 4.34 (2H, s), 7.3-7.5 (2H, m), 7.58 (1H, dt,J=1.5, 7.7 Hz), 7.89 (1H, dd, J=1.5, 7.7 Hz), 11.27 (1H, br s)

MS (m/z): 386 (M⁺), 354 (base)

Production Example 36 Ethyl5-methyl-4-oxo-2-(pyridin-2-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=6.9 Hz), 2.83 (3H, s), 4.29 (2H, q,J=6.9 Hz), 4.44 (2H, s), 7.6-7.9 (2H, m), 8.1-8.3 (1H, m), 8.72 (1H, d,J=4.6 Hz), 12.89 (1H, br s)

MS (m/z): 329 (M⁺, base)

Production Example 37 Ethyl2-benzhydryl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=6.9 Hz), 2.81 (3H, s), 4.30 (2H, q,J=6.9 Hz), 5.52 (1H, s), 7.2-7.4 (10H, m), 12.87 (1H, br s)

MS (m/z): 404 (M⁺, base)

Production Example 38 Ethyl2-(3-bromo-4-methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=6.9 Hz), 2.80 (3H, s), 3.82 (3H, s),3.90 (2H, s), 4.29 (2H, q, J=6.9 Hz), 7.07 (1H, d, J=8.5 Hz), 7.33 (1H,dd, J=2.1, 8.5 Hz), 7.60 (1H, d, J=2.1 Hz), 12.72 (1H, br s)

MS (m/z): 438 (M⁺+2), 436 (M⁺, base)

Production Example 39 Ethyl2-(2-chloro-5-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, t, J=7.1 Hz), 2.82 (3H, s), 4.27 (2H, s),4.28 (2H, q, J=7.1 Hz), 7.72 (2H, d, J=1.5 Hz), 7.91 (1H, s), 12.84 (1H,s)

MS (m/z): 432 (M⁺+2), 430 (M⁺), 395 (base)

Production Example 40 Ethyl2-(2-fluoro-3-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.1 Hz), 2.82 (3H, s), 4.16 (2H, s),4.29 (2H, q, J=7.1 Hz), 7.40 (1H, t, J=7.7 Hz), 7.6-7.8 (2H, m), 12.83(1H, br s)

MS (m/z): 414 (M⁺, base)

Production Example 41 Ethyl2-(2-fluoro-5-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.1 Hz), 2.82 (3H, s), 4.16 (2H, s),4.28 (2H, q, J=7.1 Hz), 7.45 (1H, t, J=9.1 Hz), 7.7-7.8 (1H, m), 7.9(1H, dd, J=1.9, 6.6 Hz), 12.80 (1H, br s)

MS (m/z): 414 (M⁺, base)

Production Example 42 Ethyl2-(3-chloro-2-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.1 Hz), 2.82 (3H, s), 4.11 (2H, s),4.29 (2H, q, J=7.1 Hz), 7.21 (1H, dt, J=1.0, 7.9 Hz), 7.3-7.4 (1H, m),7.4-7.6 (1H, m), 12.77 (1H, br s)

MS (m/z): 382 (M⁺+2), 380 (M⁺, base)

Production Example 43 Ethyl2-(3-chloro-4-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 2.80 (3H, s), 3.98 (2H, s),4.29 (2H, q, J=7.1 Hz), 7.3-7.5 (2H, m), 7.5-7.7 (1H, m), 12.75 (1H, brs)

MS (m/z): 382 (M⁺+2), 380 (M⁺, base)

Production Example 44 Ethyl2-(5-chloro-2-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=6.9 Hz), 2.82 (3H, s), 4.06 (2H, s),4.29 (2H, q, J=6.9 Hz), 7.26 (1H, t, J=9.1 Hz), 7.3-7.5 (1H, m), 7.52(1H, dd, J=2.7, 6.2 Hz)

MS (m/z): 382 (M⁺+2), 380 (M⁺, base)

Production Example 45 Ethyl2-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.31 (3H, t, J=7.1 Hz), 3.99 (2H, s), 4.32 (2H, q,J=7.1 Hz), 7.2-7.4 (5H, m), 7.92 (1H, s), 12.92 (1H, br s)

MS (m/z): 314 (M⁺), 91 (base)

Production Example 46 Ethyl2-(3,4-dichlorobenzyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.31 (3H, t, J=7.1 Hz), 4.03 (2H, s), 4.32 (2H, q,J=7.1 Hz), 7.36 (1H, dd, J=1.9, 8.3 Hz), 7.60 (1H, d, J=8.3 Hz), 7.66(1H, d, J=1.9 Hz), 7.92 (1H, s), 12.89 (1H, br s)

MS (m/z): 384 (M⁺+2), 382 (M⁺, base)

Production Example 47 Ethyl5-methyl-2-(2-methylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 2.30 (3H, s), 2.82 (3H, s),3.99 (2H, s), 4.29 (2H, q, J=7.1 Hz), 7.0-7.2 (4H, m), 12.73 (1H, s)

MS (m/z): 342 (M⁺)

Production Example 48 Ethyl2-(3-benzyloxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.3 Hz), 2.82 (3H, s), 4.00 (2H, s),4.29 (2H, q, J=7.3 Hz), 5.06 (2H, s), 6.9-7.0 (1H, m), 7.05 (1H, d,J=7.7 Hz), 7.2-7.3 (7H, m), 12.63 (1H, s)

MS (m/z): 434 (M⁺)

Production Example 49 Ethyl2-(4-ethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.15 (3H, t, J=7.7 Hz), 1.30 (3H, t, J=7.1 Hz), 2.57(2H, q, J=7.7 Hz), 2.81 (3H, s), 3.92 (2H, s), 4.29 (2H, q, J=7.1 Hz),7.16 (2H, d, J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz), 12.76 (1H, br s)

MS (m/z): 356 (M⁺)

Production Example 50 Ethyl2-(4-isopropylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.17 (6H, d, J=7.0 Hz), 1.30 (3H, t, J=7.1 Hz), 2.80(3H, s), 2.84 (1H, sep, J=7.0 Hz), 3.91 (2H, s), 4.29 (2H, q, J=7.1 Hz),7.19 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.3 Hz), 12.77 (1H, s)

MS (m/z): 370 (M⁺)

Production Example 51 Ethyl2-{3,5-bis(trifluoromethyl)benzyl}-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.1 Hz), 2.80 (3H, s), 4.23 (2H, s),4.28 (2H, q, J=7.1 Hz), 8.01 (1H, s), 8.11 (2H, s), 12.81 (1H, s)

MS (m/z): 464 (M⁺)

Production Example 52 Ethyl2-(3,4-difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.0 Hz), 2.81 (3H, s), 3.98 (2H, s),4.29 (2H, q, J=7.0 Hz), 7.1-7.5 (3H, m), 12.76 (1H, s)

MS (m/z): 364 (M+)

Production Example 53 Ethyl2-(2,5-difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.3 Hz), 2.82 (3H, s), 4.06 (2H, s),4.28 (2H, q, J=7.3 Hz), 7.1-7.4 (3H, m), 12.82 (1H, br s)

MS (m/z): 364 (M⁺)

Production Example 54 Ethyl5-methyl-4-oxo-2-(2-trifluoromethoxybenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.3 Hz), 2.82 (3H, s), 4.10 (2H, s),4.28 (2H, q, J=7.3 Hz), 7.3-7.5 (4H, m), 12.89 (1H, br s)

MS (m/z): 412 (M⁺)

Production Example 55 Ethyl5-methyl-4-oxo-2-(thiophen-3-yl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.32 (3H, t, J=7.3 Hz), 2.86 (3H, s), 4.31 (2H, q,J=7.3 Hz), 7.72 (1H, dd, J=3.1, 5.0 Hz), 7.8-7.9 (1H, m), 8.6-8.7 (1H,m), 12.71 (1H, s)

MS (m/z): 320 (M⁺)

Production Example 56 Ethyl2-(4-hydroxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 2.80 (3H, s), 3.82 (2H, s),4.29 (2H, q, J=7.1 Hz), 6.71 (2H, d, J=8.5 Hz), 7.14 (2H, d, J=8.5 Hz),9.32 (1H, s), 12.70 (1H, s)

MS (m/z): 344 (M⁺)

Production Example 57 Ethyl2-(5-bromo-2-methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.3 Hz), 2.82 (3H, s), 3.72 (3H, s),4.00 (2H, s), 4.29 (2H, q, J=7.3 Hz), 6.97 (1H, d, J=8.5 Hz), 7.4-7.5(2H, m), 12.68 (1H, br s)

MS (m/z): 438 (M⁺+2), 436 (M⁺)

Production Example 58 Ethyl2-(3-fluoro-5-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.3 Hz), 2.81 (3H, s), 4.12 (2H, s),4.29 (2H, q, J=7.3 Hz), 7.0-7.7 (3H, m), 12.79 (1H, br s)

MS (m/z): 414 (M⁺)

Production Example 59 Ethyl2-(2-ethoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.18 (3H, t, J=6.9 Hz), 1.29 (3H, t, J=7.3 Hz), 2.82(3H, s), 3.94 (2H, s), 3.95 (2H, q, J=6.9 Hz), 4.28 (2H, q, J=7.3 Hz),6.8-6.9 (2H, m), 7.1-7.3 (2H, m), 12.74 (1H, br s).

MS (m/z): 372 (M+).

Production Example 60 Ethyl5-methyl-4-oxo-2-phenyl-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.32 (3H, t, J=7.0 Hz), 2.87 (3H, s), 4.32 (2H, q,J=7.0 Hz), 7.5-7.7 (3H, m), 8.1-8.2 (2H, m), 12.80 (1H, s)

MS (m/z): 314 (M⁺)

Production Example 61 Ethyl5-methyl-4-oxo-2-phenoxy-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.27 (3H, t, J=7.3 Hz), 2.80 (3H, s), 4.26 (2H, q,J=7.3 Hz), 7.2-7.6 (5H, m), 13.03 (1H, s)

MS (m/z): 330 (M⁺)

Production Example 62 Ethyl2-(4-butoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 0.92 (3H, t, J=6.9 Hz), 1.30 (3H, t, J=7.0 Hz), 1.41(2H, sex, J=6.9 Hz), 1.67 (2H, quin, J=6.9 Hz), 2.80 (3H, s), 3.87 (2H,s), 3.93 (2H, t, J=6.9 Hz), 4.29 (2H, q, J=7.0 Hz), 6.87 (2H, d, J=8.4Hz), 7.25 (2H, d, J=8.4 Hz), 12.73 (1H, s)

MS (m/z): 400 (M⁺)

Production Example 63 Ethyl2-(4-tert-butylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.25 (9H, s), 1.30 (3H, t, J=7.1 Hz), 2.80 (3H, s),3.91 (2H, s), 4.29 (2H, q, J=7.1 Hz), 7.28 (2H, d, J=8.1 Hz), 7.35 (2H,d, J=8.1 Hz), 12.76 (1H, br s)

MS (m/z): 384 (M⁺)

Production Example 64 Ethyl2-(4-fluoro-3-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 2.81 (3H, s), 4.07 (2H, s), 4.28 (2H, q, J=7.3 Hz),7.1-7.2 (2H, m), 7.76 (1H, s), 12.77 (1H, br s)

MS (m/z): 414 (M⁺)

Production Example 65 Ethyl2-(2,4-difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, t, J=7.3 Hz), 2.82 (3H, s), 4.09 (2H, s),4.28 (2H, q, J=7.3 Hz), 7.1-7.2 (2H, m), 7.4-7.5 (1H, m), 12.87 (1H, brs)

MS (m/z): 364 (M⁺)

Production Example 66 Ethyl2-(2-chloro-6-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, t, J=7.3 Hz), 2.82 (3H, s), 4.19 (2H, s),4.28 (2H, q, J=7.3 Hz), 7.2-7.4 (3H, m), 12.89 (1H, br s)

MS (m/z): 380 (M⁺)

Production Example 67 Ethyl2-(2,6-difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=6.9 Hz), 2.81 (3H, s), 4.03 (2H, s),4.29 (2H, q, J=6.9 Hz), 7.0-7.1 (1H, m), 7.2-7.3 (1H, m), 7.4-7.5 (1H,m), 12.77 (1H, br s)

MS (m/z): 364 (M⁺)

Production Example 68 Ethyl5-methyl-4-oxo-2-phenylamino-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.3 Hz), 2.71 (3H, s), 4.25 (2H, q,J=7.3 Hz), 7.3-7.4 (2H, m), 7.5-7.6 (3H, m)

MS (m/z): 329 (M⁺)

Production Example 69 Ethyl5-methyl-4-oxo-2-(2-trifluoromethylthiobenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.0 Hz), 2.83 (3H, s), 4.29 (2H, q,J=7.0 Hz), 4.33 (2H, s), 7.4-7.6 (4H, m), 12.82 (1H, s)

MS (m/z): 428 (M⁺)

Production Example 70 Ethyl5-methyl-4-oxo-2-(2,3,5-trifluorobenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.3 Hz), 2.82 (3H, s), 4.12 (2H, s),4.29 (2H, q, J=7.3 Hz), 7.1-7.3 (1H, m), 7.4-7.6 (1H, m), 12.82 (1H, s)

MS (m/z): 382 (M⁺)

Production Example 71 Ethyl5-methyl-4-oxo-2-(4-trifluoromethoxybenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.3 Hz), 2.81 (3H, s), 4.01 (2H, s),4.29 (2H, q, J=7.3 Hz), 7.33 (2H, d, J=8.9 Hz), 7.49 (2H, d, J=8.9 Hz),12.79 (1H, br s)

MS (m/z): 412 (M⁺)

Production Example 72 Ethyl5-methyl-4-oxo-2-(3-trifluoromethoxybenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.3 Hz), 2.81 (3H, s), 4.04 (2H, s),4.29 (2H, q, J=7.3 Hz), 7.2-7.5 (4H, m)

MS (m/z): 412 (M⁺)

Production Example 73 Ethyl2-(2-benzyloxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.3 Hz), 2.86 (3H, s), 4.00 (2H, s),4.29 (2H, q, J=7.3 Hz), 5.06 (2H, s), 7.2-7.3 (9H, m), 12.62 (1H, br s)

MS (m/z): 434 (M⁺)

Production Example 74 Ethyl5-methyl-2-(4-methylthiobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.3 Hz), 2.45 (3H, s), 2.81 (3H, s),3.92 (2H, s), 4.29 (2H, q, J=7.3 Hz), 7.2-7.4 (4H, m)

MS (m/z): 374 (M⁺)

Production Example 75 Ethyl2-(5-fluoro-2-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.29 (3H, t, J=7.3 Hz), 2.83 (3H, s), 4.26 (2H, s),4.29 (2H, q, J=7.3 Hz), 7.3-7.5 (2H, m), 7.8-7.9 (1H, m), 12.83 (1H, s)

MS (m/z): 414 (M⁺)

Production Example 76 Ethyl2-(3-chlorobenzyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.31 (3H, t, J=7.1 Hz), 4.01 (2H, s), 4.32 (2H, q,J=7.1 Hz), 7.2-7.4 (4H, m), 7.92 (1H, s), 12.91 (1H, br s)

MS (m/z): 348 (M⁺)

Production Example 77 Ethyl4-oxo-2-(thiophen-3-ylmethyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.31 (3H, t, J=7.1 Hz), 4.01 (2H, s), 4.32 (2H, q,J=7.1 Hz), 7.2-7.4 (3H, m), 7.92 (1H, s), 12.91 (1H, br s)

MS (m/z): 320 (M⁺)

Production Example 78 Ethyl2-(cyclopent-1-enylmethyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.31 (3H, t, J=7.1 Hz), 1.83 (2H, quin, J=7.5 Hz),2.2-2.3 (4H, m), 3.44 (2H, s), 4.33 (2H, q, J=7.1 Hz), 5.4-5.5 (1H, m),7.92 (1H, s), 12.70 (1H, br s)

MS (m/z): 304 (M⁺)

Production Example 79 Ethyl4-oxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

¹H-NMR (DMSO-d₆) δ: 1.31 (3H, t, J=7.1 Hz), 4.12 (2H, s), 4.32 (2H, q,J=7.1 Hz), 7.5-7.6 (4H, m), 7.92 (1H, s), 12.91 (1H, br s)

MS (m/z): 382 (M⁺)

Production Example 80 Ethyl4-chloro-2-(3,4-dichlorobenzyl)-5-methylthieno-[2,3-d]pyrimidine-6-carboxylate

Three (3.00) g of ethyl2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateand 37 mL of phosphorus oxychloride were mixed, and to which 1.4 mL ofN,N-dimethylaniline was added, followed by stirring at 90° for 4 hours.The reaction liquid was poured on ice and stirred for 3 hours, and theprecipitated crystals were recovered by filtration and washed withwater. Drying the crystals under aeration, 3.05 g of the title compoundwas obtained.

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, t, J=7.1 Hz), 3.02 (3H, s), 4.26 (2H, s),4.41 (2H, q, J=7.1 Hz), 7.23 (1H, dd, J=1.9, 8.1 Hz), 7.37 (1H, d, J=8.1Hz), 7.48 (1H, d, J=1.9 Hz)

MS (m/z): 416 (M⁺+2), 414 (M⁺), 159 (base)

Production Example 81 Ethyl2-(3,4-dichlorobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

A mixture of 1.23 g of ethyl4-chloro-2-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate,594 mg of thiourea and 50 mL of ethanol was stirred at room temperaturefor 35 hours. Then 50 mL of water was added, followed by 30 minutes'stirring. Crystals were recovered by filtration and washed with water.Drying the same under aeration, 1.15 g of the title compound wasobtained.

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 3.06 (3H, s), 4.13 (2H, s),4.31 (2H, q, J=7.1 Hz), 7.35 (1H, dd, J=2.1, 8.3 Hz), 7.60 (1H, d, J=8.3Hz), 7.67 (1H, d, J=2.1 Hz), 14.00 (1H, br s)

MS (m/z): 414 (M⁺+2), 412 (M⁺), 383 (base)

Production Example 82 Ethyl2-(3-bromobenzyl)-4-chloro-5-methylthieno-[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 80.

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, t, J=7.1 Hz), 3.02 (3H, s), 4.28 (2H, s),4.31 (2H, q,=7.1 Hz), 7.17 (1H, t, J=7.7 Hz), 7.2-7.4 (2H, m), 7.5-7.6(1H, m)

MS (m/z): 426 (M⁺+2), 424 (M⁺), 169 (base)

Production Example 83 Ethyl2-(3-bromobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 81.

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 3.07 (3H, s), 4.12 (2H, s),4.31 (2H, q, J=7.1 Hz), 7.2-7.4 (2H, m), 7.4-7.5 (1H, m), 7.5-7.7 (1H,m), 14.02 (1H, br s)

MS (m/z): 424 (M⁺+2), 422 (M⁺), 395 (base)

Production Example 84 Ethyl4-chloro-5-methyl-2-(thiophen-2-ylmethyl)thieno-[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 80.

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, t, J=7.1 Hz), 3.02 (3H, s), 4.41 (2H, q,J=7.1 Hz), 4.52 (2H, s), 6.94 (1H, dd, J=3.5, 5.0 Hz), 7.0-7.1 (1H, m),7.19 (1H, dd, J=1.3, 5.0 Hz)

MS (m/z): 352 (M⁺), 97 (base)

Production Example 85 Ethyl5-methyl-2-(thiophen-2-ylmethyl)-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 81.

¹H-NMR (DMSO-d₆) δ: 1.31 (3H, t, J=7.1 Hz), 3.07 (3H, s), 4.32 (2H, s),4.32 (2H, q, J=7.1 Hz), 6.99 (1H, dd, J=3.5, 5.0 Hz), 7.05 (1H, dd,J=1.2, 3.5 Hz), 7.43 (1H, dd, J=1.2, 5.0 Hz), 14.05 (1H, br s)

MS (m/z): 350 (M⁺), 97 (base)

Production Example 86 Ethyl4-chloro-5-methyl-2-(thiophen-3-ylmethyl)thieno-[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 80.

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, t, J=7.1 Hz), 3.02 (3H, s), 4.34 (2H, s),4.41 (2H, q, J=7.1 Hz), 7.13 (1H, dd, J=1.2, 5.0 Hz), 7.1-7.3 (2H, m)

MS (m/z): 354 (M⁺+2), 352 (M⁺), 97 (base)

Production Example 87 Ethyl5-methyl-2-(thiophen-3-ylmethyl)-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 81.

¹H-NMR (DMSO-d₆) δ: 1.31 (3H, t, J=6.9 Hz), 3.07 (3H, s), 4.11 (2H, s),4.31 (2H, q, J=6.9 Hz), 7.10 (1H, dd, J=1.2, 5.0 Hz), 7.3-7.4 (1H, m),7.4-7.6 (1H, m), 13.99 (1H, br s)

MS (m/z): 350 (M⁺), 97 (base)

Production Example 88 Ethyl4-chloro-2-(cyclohex-1-enylmethyl)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 80.

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, t, J=7.1 Hz), 1.5-1.7 (4H, m), 1.9-2.1(4H, m), 3.03 (3H, s), 3.64 (2H, s), 4.41 (2H, q, J=7.1 Hz), 5.4-5.5(1H, m)

MS (m/z): 352 (M⁺+2), 350 (M⁺), 308 (base)

Production Example 89 Ethyl2-(cyclohex-1-enylmethyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 81.

¹H-NMR (DMSO-d₆) δ: 1.31 (3H, t, J=6.9 Hz), 1.4-1.7 (4H, m), 1.8-2.1(4H, m), 3.07 (3H, s), 3.39 (2H, s), 4.32 (2H, q, J=7.1 Hz), 5.4-5.6(1H, m), 13.77 (1H, br s)

MS (m/z): 348 (M⁺, base)

Production Example 90 Ethyl2-benzyl-4-chloro-5-methylthieno-[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 80.

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, t, J=7.1 Hz), 3.01 (3H, s), 4.32 (2H, s),4.40 (2H, q, J=7.1 Hz), 7.1-7.5 (5H, m)

MS (m/z): 345 (M⁺), 91 (base)

Production Example 91 Ethyl2-benzyl-5-methyl-4-thioxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 81.

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=6.9 Hz), 3.06 (3H, s), 4.11 (2H, s),4.31 (2H, q, J=6.9 Hz), 7.2-7.4 (5H, m), 14.03 (1H, br s)

MS (m/z): 344 (M⁺), 315 (base)

Production Example 92 Ethyl4-chloro-2-(3-chlorobenzyl)-5-methylthieno-[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 80.

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, t, J=7.1 Hz), 3.02 (3H, s), 4.29 (2H, s),4.31 (2H, q, J=7.1 Hz), 7.1-7.3 (3H, m), 7.3-7.4 (1H, m)

MS (m/z): 380 (M⁺), 125 (base)

Production Example 93 Ethyl2-(3-chlorobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 81.

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 3.06 (3H, s), 4.13 (2H, s),4.31 (2H, q, J=7.1 Hz), 7.2-7.5 (4H, m), 14.02 (1H, br s)

MS (m/z): 380 (M⁺+2), 378 (M⁺), 349 (base)

Production Example 94 Ethyl4-chloro-2-(3-chloro-4-fluorobenzyl)-5-methylthieno-[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 80.

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, t, J=7.1 Hz), 3.02 (3H, s), 4.26 (2H, s),4.41 (2H, q, J=7.1 Hz), 7.06 (1H, t, J=8.7 Hz), 7.2-7.3 (1H, m), 7.43(1H, dd, J=2.3, 6.9 Hz)

MS (m/z): 400 (M⁺+2), 398 (M⁺), 143 (base)

Production Example 95 Ethyl2-(3-chloro-4-fluorobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 81.

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 3.06 (3H, s), 4.12 (2H, s),4.31 (2H, q, J=7.1 Hz), 7.3-7.5 (2H, m), 7.5-7.7 (1H, m), 14.00 (1H, brs)

MS (m/z): 398 (M⁺+2), 396 (M⁺), 367 (base)

Production Example 96 Ethyl4-chloro-5-methyl-2-(3-trifluoromethylbenzyl)thieno-[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 80.

¹H-NMR (DMSO-d₆) δ: 1.41 (3H, t, J=7.3 Hz), 3.02 (3H, s), 4.37 (2H, s),4.40 (2H, q, J=7.3 Hz), 7.3-7.6 (3H, m), 7.67 (1H, s)

MS (m/z): 414 (M⁺), 159 (base)

Production Example 97 Ethyl5-methyl-4-thioxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 81.

¹H-NMR (DMSO-d₆) δ: 1.30 (3H, t, J=7.1 Hz), 3.06 (3H, s), 4.23 (2H, s),4.31 (2H, q, J=7.1 Hz), 7.5-7.7 (3H, m), 7.78 (1H, s), 14.05 (1H, br s)

MS (m/z): 412 (M⁺), 383 (base)

Production Example 98 Ethyl4-chloro-2-(3,4-dichlorobenzyl)thieno-[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 80.

¹H-NMR (CDCl₃) δ: 1.42 (3H, t, J=7.3 Hz), 4.29 (2H, s), 4.44 (2H, q,J=7.3 Hz), 7.2-7.3 (1H, m), 7.37 (1H, d, J=8.5 Hz), 7.50 (1H, d, J=1.9Hz), 8.05 (1H, s)

MS (m/z): 401 (M⁺+1), 159 (base)

Production Example 99 Ethyl2-(3,4-dichlorobenzyl)-4-thioxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 81.

¹H-NMR (DMSO-d₆) δ: 1.32 (3H, t, J=7.1 Hz), 4.16 (2H, s), 4.33 (2H, q,J=7.1 Hz), 7.37 (1H, dd, J=1.9, 8.3 Hz), 7.61 (1H, d, J=8.3 Hz), 7.68(1H, d, J=1.9 Hz), 8.06 (1H, s), 14.27 (1H, br s)

MS (m/z): 400 (M⁺+2), 398 (M⁺, base)

Production Example 100 Ethyl2-benzyl-4-chlorothieno[2,3-d]pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 80.

¹H-NMR (DMSO-d₆) δ: 1.42 (3H, t, J=7.1 Hz), 4.35 (2H, s), 4.43 (2H, q,J=7.1 Hz), 7.2-7.5 (5H, m), 8.04 (1H, s)

MS (m/z): 331 (M⁺−1), 91 (base)

Production Example 101 Ethyl2-benzyl-4-thioxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylate

The title compound was obtained in the manner similar to ProductionExample 81.

¹H-NMR (DMSO-d₆) δ: 1.32 (3H, t, J=7.1 Hz), 4.13 (2H, s), 4.34 (2H, q,J=7.1 Hz), 7.2-7.4 (5H, m), 8.06 (1H, s), 14.30 (1H, br s)

MS (m/z): 330 (M⁺, base)

Production Example 102 Ethyl2-(3-chlorobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylate

The compound of Production Example 93 was prepared by a different methodas follows. A mixture of 5.007 g of ethyl 2-3(3-chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate,4.913 g of2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphophetan-2,4-disulfide and125 mL of dioxane was heated under reflux for 4.5 hours. Five (5) mL ofwater and 24.2 mL of aqueous sodium hydroxide solution were added to thereaction liquid and stirred. Further 100 mL of water was added andcooled with ice. Whereupon precipitated crystals were recovered byfiltration and washed with water. Drying the crystals under aeration,5.415 g of the title compound was obtained.

Example 15-Methyl-4-oxo-2-(thiophen-3-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

A mixture of 379 mg of ethyl5-methyl-4-oxo-2-(thiophen-3-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 1, 3.4 mL of 1N aqueous sodiumhydroxide solution and 2.2 mL of ethanol was heated under reflux for 2hours. After cooling off, the reaction liquid was poured on ice,rendered acidic with diluted hydrochloric acid, and the precipitatedcrystals were recovered by filtration. After washing with water, thecrystals were dried by heating under reduced pressure, to provide 320 mgof5-methyl-4-oxo-2-(thiophen-3-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.96 (2H, s), 7.0-7.6 (3H, m), 12.69(1H, br s), 13.32 (1H, br s)

MS (m/z): 306 (M⁺)

Compounds of Examples 2-68 were synthesized in the manner similar toExample 1.

Example 25-Methyl-4-oxo-2-(thiophen-2-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(thiophen-2-ylmethyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 2, in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 4.17 (2H, s), 6.9-7.5 (3H, m), 12.75(1H, br s), 13.35 (1H, br s)

MS (m/z): 306 (M⁺)

Example 32-(5-Chlorothiophen-2-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(5-chlorothiophen-2-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 3, in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 4.13 (2H, s), 6.91 (1H, d, J=3.9 Hz),6.98 (1H, d, J=3.9 Hz), 12.74 (1H, br s), 13.37 (1H, br s)

MS (m/z): 342 (M⁺+2), 340 (M⁺)

Example 45-Methyl-2-(4-methylthiazol-2-ylmethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(4-methylthiazol-2-ylmethyl)-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 4, in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 2.32 (3H, d, J=0.8 Hz), 2.81 (3H, s), 4.36 (2H, s),7.21 (1H, d, J=0.8 Hz), 12.80 (1H, br s), 13.37 (1H, br s)

MS (m/z): 321 (M⁺)

Example 55-Methyl-4-oxo-2-(pyridin-3-ylmethyl)-3,4-dihydrothieno[2,3-d]pyridine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(pyridin-3-ylmethyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized similarly to Production Example 36, in the manner similarto Example 1.

MS (m/z): 301 (M⁺), 257 (base)

Example 62-(2-Fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 5, in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.04 (2H, s), 7.1-7.5 (4H, m), 12.74(1H, br s), 13.35 (1H, br s)

MS (m/z): 318 (M⁺)

Example 72-(3-Fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 6, in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.99 (2H, s), 7.0-7.5 (4H, m), 12.74(1H, br s), 13.34 (1H, br s)

MS (m/z): 318 (M⁺)

Example 82-(4-Fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(4-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized similarly to Production Example 6, in the manner similarto Example 1.

¹H-NMR (DMSO-d₆) δ: 2.78 (3H, s), 3.95 (2H, s), 7.1-7.2 (2H, m), 7.3-7.5(2H, m), 12.72 (1H, s)

MS (m/z): 318 (M⁺, base)

Example 92-(2-Chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized similarly to Production Example 7, in the manner similarto Example 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.14 (2H, s), 7.3-7.5 (4H, m), 12.76(1H, br s), 13.33 (1H, br s)

MS (m/z): 336 (M⁺+2), 334 (M⁺)

Example 10-a)2-(3-Chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 7, in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.98 (2H, s), 7.2-7.4 (3H, m), 7.45(1H, s), 12.72 (1H, br s), 13.33 (1H, br s)

MS (m/z): 336 (M⁺+2), 334 (M⁺)

Example 10-b)2-(3-Chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid sodium salt

Sodium salt of the compound which was synthesized in above Example 10-a)was obtained.

¹H-NMR (DMSO-d₆) δ: 2.73 (3H, s), 3.92 (2H, s), 7.2-7.4 (3H, m), 7.44(1H, s), 12.34 (1H, br s)

Example 10-c)2-(3-Chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid sodium salt.½ ethanolate

Sodium salt.½ ethanolated product of the compound which was synthesizedin above Example 10-a) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.06 (1.5H, t, J=7.0 Hz), 2.73 (3H, s), 3.44 (1H, q,J=6.9 Hz), 3.92 (2H, s), 4.34 (0.5H, br s).7.2-7.4 (3H, m), 7.44 (1H,s), 12.32 (1H, br s)

(The underlined part is the peak attributable to ethanol.)

Example 112-(4-Chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(4-chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized similarly to Production Example 7, in the manner similarto Example 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.96 (2H, s), 7.3-7.5 (4H, m), 12.71(1H, br s), 13.34 (1H, br s)

MS (m/z): 336 (M⁺+2), 334 (M⁺)

Example 122-(3-Bromobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-bromobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 11, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.97 (2H, s), 7.2-7.7 (4H, m), 12.71(1H, br s), 13.34 (1H, br s)

MS (m/z): 380 (M⁺+2), 378 (M⁺)

Example 132-(4-Bromobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(4-bromobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 12, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.78 (3H, s), 3.94 (2H, s), 7.2-7.6 (4H, m), 12.67(1H, br s)

MS (m/z): 380 (M⁺+2), 378 (M⁺)

Example 145-Methyl-2-(2-methylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(2-methylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 47, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.29 (3H, s), 2.80 (3H, s), 3.98 (2H, s), 7.1-7.2(4H, m), 12.67 (1H, br s), 13.31 (1H, br s)

MS (m/z): 314 (M⁺)

Example 155-Methyl-2-(3-methylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(3-methylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 13, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.28 (3H, s), 2.79 (3H, s), 3.91 (2H, s), 7.0-7.3(4H, m), 12.69 (1H, br s), 13.32 (1H, br s)

MS (m/z): 314 (M⁺)

Example 165-Methyl-2-(4-methylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(4-methylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 14, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.26 (3H, s), 2.78 (3H, s), 3.90 (2H, s), 7.0-7.3(4H, m), 12.68 (1H, br s), 13.31 (1H, br s)

MS (m/z): 314 (M⁺)

Example 172-(2,6-Dimethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2,6-dimethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylatewhich was synthesized similarly to Production Example 14, in the mannersimilar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.24 (6H, s), 2.80 (3H, s), 4.40 (2H, s), 7.0-7.1(3H, m), 12.70 (1H, br s), 13.25 (1H, br s)

MS (m/z): 328 (M⁺)

Example 182-(4-Ethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(4-ethylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 49, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 1.15 (3H, t, J=7.7 Hz), 2.56 (2H, q, J=7.7 Hz), 2.78(3H, s), 3.90 (2H, s), 7.16 (2H, d, J=8.1 Hz), 7.26 (2H, d, J=8.1 Hz),12.70 (1H, br s), 13.32 (1H, br s)

MS (m/z): 328 (M⁺)

Example 192-(4-Isopropylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(4-isopropylbenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 50, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 1.17 (6H, d, J=7.0 Hz), 2.78 (3H, s), 2.85 (1H, sep,J=7.0 Hz), 3.90 (2H, s), 7.19 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz),12.69 (1H, br s), 13.32 (1H, br s)

MS (m/z): 342 (M⁺)

Example 202-(4-tert-Butylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(4-tert-butylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 63, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 1.24 (9H, s), 2.75 (3H, s), 3.87 (2H, s), 7.2-7.4(4H, m), 12.45 (1H, br s)

MS (m/z): 356 (M⁺)

Example 215-Methyl-4-oxo-2-(2-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(2-trifluoromethylbenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 15, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.23 (2H, s), 7.4-7.8 (4H, m), 12.77(1H, br s), 13.32 (1H, br s)

MS (m/z): 368 (M⁺)

Example 225-Methyl-4-oxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 16, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 4.08 (2H, s), 7.5-7.7 (3H, m), 7.76(1H, s), 12.75 (1H, br s), 13.34 (1H, br s)

MS (m/z): 368 (M⁺)

Example 235-Methyl-4-oxo-2-(4-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(4-trifluoromethylbenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 17, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 4.08 (2H, s), 7.5-7.8 (4H, m), 12.77(1H, br s), 13.34 (1H, br s)

MS (m/z): 368 (M⁺)

Example 242-(4-Hydroxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(4-hydroxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 56, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.78 (3H, s), 3.81 (2H, s), 6.6-6.7 (2H, m), 7.1-7.2(2H, m), 9.31 (1H, br s), 12.63 (1H, br s), 13.31 (1H, br s)

MS (m/z): 316 (M⁺)

Example 252-(2-Methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized similarly to Production Example 59, in the manner similarto Example 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.73 (3H, s), 3.93 (2H, s), 6.8-7.0(1H, m), 6.98 (1H, d, J=7.9 Hz), 7.16 (1H, dd, J=1.5, 7.5 Hz), 7.2-7.3(1H, m), 12.58 (1H, s)

MS (m/z): 330 (M⁺), 299 (base)

Example 262-(3-Methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylatewhich was synthesized similarly to Production Example 59, in the mannersimilar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.78 (3H, s), 3.73 (3H, s), 3.90 (2H, s), 6.82 (1H,dd, J=1.9, 8.1 Hz), 6.90 (1H, d, J=7.4 Hz), 6.94 (1H, s), 7.23 (1H, t,J=7.7 Hz), 12.64 (1H, br s)

MS (m/z): 330 (M⁺, base)

Example 275-Methyl-4-oxo-2-(2-trifluoromethoxybenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(2-trifluoromethoxybenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 54, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.09 (2H, s), 7.3-7.5 (4H, m), 12.78(1H, br s), 13.32 (1H, br s)

MS (m/z): 384 (M⁺)

Example 285-Methyl-4-oxo-2-(3-trifluoromethoxybenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(3-trifluoromethoxybenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 72, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 4.03 (2H, s), 7.2-7.3 (1H, m), 7.3-7.4(2H, m), 7.4-7.5 (1H, m), 12.33 (1H, br s)

MS (m/z): 384 (M⁺)

Example 295-Methyl-4-oxo-2-(4-trifluoromethoxybenzyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(4-trifluoromethoxybenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 71, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.78 (3H, s), 4.00 (2H, s), 7.33 (2H, d, J=8.1 Hz),7.48 (2H, d, J=8.1 Hz), 12.71 (1H, br s), 13.32 (1H, br s)

MS (m/z): 384 (M+)

Example 302-(2-(Benzyloxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-benzyloxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 73, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.81 (3H, s), 4.00 (2H, s), 5.12 (2H, s), 6.9-7.0(1H, m), 7.02 (1H, d, J=7.7 Hz), 7.2-7.3 (3H, m), 7.3-7.4 (2H, m), 7.52(2H, d, J=7.3 Hz), 12.33 (1H, br s)

MS (m/z): 406 (M⁺)

Example 312-(3-Benzyloxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-benzyloxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 48, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.91 (2H, s), 5.08 (2H, s), 6.8-7.5(9H, m), 12.70 (1H, br s), 13.32 (1H, br s)

MS (m/z): 406 (M⁺)

Example 322-(2-Ethoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-ethoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 59, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 1.18 (3H, t, J=7.0 Hz), 2.80 (3H, s), 3.94 (2H, s),3.96 (2H, q, J=7.0 Hz), 6.8-6.9 (2H, m), 7.1-7.2 (2H, m), 12.58 (1H, brs), 13.28 (1H, br s)

MS (m/z): 344 (M⁺)

Example 332-(4-Butoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(4-butoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 62, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 0.92 (3H, t, J=7.3 Hz), 1.4-1.5 (2H, m), 1.6-1.7(2H, m), 2.78 (3H, s), 3.86 (2H, s), 3.93 (2H, t, J=6.6 Hz), 6.8-6.9(2H, m), 7.2-7.3 (2H, m), 12.67 (1H, br s), 13.31 (1H, br s)

MS (m/z): 372 (M⁺)

Example 342-(2,3-Dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2,3-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 8, in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.21 (2H, s), 7.3-7.7 (3H, m), 12.77(1H, br s), 13.33 (1H, br s)

MS (m/z): 370 (M⁺+2), 368 (M⁺)

Example 352-(2,4-Dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 9, in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.14 (2H, s), 7.3-7.7 (3H, m), 12.77(1H, br s), 13.33 (1H, br s)

MS (m/z): 370 (M⁺+2), 368 (M⁺)

Example 36-a)2-(3,4-Dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 10, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.99 (2H, s), 7.3-7.7 (3H, m), 12.71(1H, br s), 13.33 (1H, br s)

MS (m/z): 370 (M⁺+2), 368 (M⁺)

Example 36-b)2-(3,4-Dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid sodium salt

A sodium salt of the compound as synthesized in above Example 36-a) wasobtained.

¹H-NMR (DMSO-d₆) δ: 2.73 (3H, s), 3.93 (2H, s), 7.34 (1H, dd, J=1.9, 8.5Hz), 7.59 (1H, d, J=8.5 Hz), 7.64 (1H, d, J=1.9 Hz), 12.31 (1H, br s)

Example 36-c)2-(3,4-Dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid sodium salt.½ ethanolate

A sodium salt.½ ethanolate of the compound as synthesized in aboveExample 36-a) was obtained.

¹H-NMR (DMSO-d₆) δ: 1.06 (1.5H, t, J=7.0 Hz), 2.73 (3H, s), 3.4-3.5 (1H,m), 3.93 (2H, s), 4.34 (0.5H, br t), 7.34 (1H, dd, J=1.9, 8.5 Hz), 7.59(1H, d, J=8.5 Hz), 7.64 (1H, d, J=1.9 Hz), 12.31 (1H, br s)

(The underlined part is the peak attributable to ethanol.)

Example 372-(3,4-Dimethoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3,4-dimethoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylatewhich was synthesized similarly to Production Example 59, in the mannersimilar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.77 (3H, s), 3.70 (3H, s), 3.73 (3H, s), 3.89 (2H,s), 6.8-7.0 (2H, m), 6.99 (1H, d, J=2.0 Hz), 12.63 (1H, s)

MS (m/z): 360 (M⁺, base)

Example 385-Methyl-2-(3,4-methylenedioxybenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(3,4-methylenedioxybenzyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to Production Example 59, in the mannersimilar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 3.89 (2H, s), 6.00 (2H, s), 6.8-6.9(2H, m), 6.98 (1H, s)

MS (m/z): 344 (M⁺, base)

Example 395-Methyl-2-(4-methylthiobenzyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(4-methylthiobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 74 in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 2.44 (3H, s), 2.78 (3H, s), 3.91 (2H, s), 7.22 (2H,d, J=8.5 Hz), 7.30 (2H, d, J=8.5 Hz), 12.51 (1H, br s), 12.69 (1H, br s)

MS (m/z): 346 (M⁺)

Example 405-Methyl-4-oxo-2-(2-trifluoromethylthiobenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(2-trifluoromethylthiobenzyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 69 in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.32 (2H, s), 7.4-7.6 (3H, m), 7.7-7.8(1H, m), 12.77 (1H, br s), 13.32 (1H, br s)

MS (m/z): 400 (M⁺)

Example 412-(2-Carboxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-methoxycarbonylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 35, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.36 (2H, s), 7.3-7.5 (2H, m), 7.55(1H, dt, J=1.5, 7.7 Hz), 7.91 (1H, dd, J=1.5, 7.7 Hz), 12.62 (1H, br s),13.04 (1H, br s)

MS (m/z): 344 (M⁺), 326 (base)

Example 422-(Biphenyl-4-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(biphenyl-4-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized similarly to Production Example 37, in the manner similarto Example 1.

¹H-NMR (DMSO-d₆) δ: 2.78 (3H, s), 4.00 (2H, s), 7.3-7.4 (1H, m), 7.4-7.5(4H, m), 7.5-7.7 (4H, m), 12.77 (1H, s)

MS (m/z): 376 (M⁺, base)

Example 432-(3-Bromo-4-methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-bromo-4-methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 38, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.82 (3H, s), 3.89 (2H, s), 7.07 (1H,d, J=8.5 Hz), 7.33 (1H, dd, J=1.9, 8.5 Hz), 7.60 (1H, d, J=1.9 Hz),12.67 (1H, br s), 13.33 (1H, br s)

MS (m/z): 410 (M⁺+2), 408 (M⁺), 183 (base)

Example 442-(5-Bromo-2-methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(5-bromo-2-methoxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 57, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 3.72 (3H, s), 3.94 (2H, s), 6.97 (1H,d, J=8.9 Hz), 7.4-7.5 (2H, m), 12.62 (1H, br s), 13.31 (1H, br s)

MS (m/z): 410 (M⁺+2), 408 (M⁺)

Example 452-(2-Chloro-5-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-chloro-5-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 39, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.27 (2H, s), 7.72 (2H, d, J=1.5 Hz),7.90 (1H, s), 12.80 (1H, br s), 13.33 (1H, br s)

MS (m/z): 404 (M⁺+2), 402 (M⁺), 367 (base)

Example 462-(2-Fluoro-3-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-fluoro-3-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 40, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.15 (2H, s), 7.3-7.5 (1H, m), 7.6-7.8(2H, m), 12.78 (1H, s), 13.33 (1H, s)

MS (m/z): 386 (M⁺)

Example 472-(2-Fluoro-5-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-fluoro-5-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 41, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.16 (2H, s), 7.45 (1H, t, J=9.1 Hz),7.7-7.8 (1H, m), 7.90 (1H, dd, J=2.1, 6.7 Hz), 12.77 (1H, br s), 13.36(1H, br s)

MS (m/z): 386 (M⁺, base)

Example 482-(3-Fluoro-5-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-fluoro-5-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 58, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 4.13 (2H, s), 7.5-7.6 (3H, m), 12.76(1H, br s), 13.34 (1H, br s)

MS (m/z): 386 (M⁺)

Example 492-(4-Fluoro-3-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(4-fluoro-3-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 64, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 4.07 (2H, s), 7.4-7.5 (1H, m), 7.6-7.8(1H, m), 7.8-7.9 (1H, m), 12.73 (1H, br s), 13.34 (1H, br s)

MS (m/z): 386 (M⁺)

Example 502-(5-Fluoro-2-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(5-fluoro-2-trifluoromethylbenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 75, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.25 (2H, s), 7.3-7.5 (2H, m), 7.8-7.9(1H, m), 12.76 (1H, s), 13.35 (1H, br s)

MS (m/z): 386 (M⁺)

Example 512-(3-Chloro-2-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-chloro-2-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 42, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.10 (2H, s), 7.21 (1H, dt, J=1.0, 7.9Hz), 7.3-7.4 (1H, m), 7.4-7.6 (1H, m), 12.76 (1H, br s), 13.34 (1H, brs)

MS (m/z): 354 (M⁺+2), 352 (M⁺), 143 (base)

Example 522-(3-Chloro-4-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-chloro-4-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 43, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.97 (2H, s), 7.3-7.5 (2H, m), 7.5-7.7(1H, m), 12.69 (1H, br s), 13.34 (1H, br s)

MS (m/z): 354 (M⁺+2), 352 (M⁺), 183 (base)

Example 532-(5-Chloro-2-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(5-chloro-2-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 44, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.05 (2H, s), 7.26 (1H, t, J=9.1 Hz),7.3-7.5 (1H, m), 7.52 (1H, dd, J=2.7, 6.2 Hz), 12.73 (1H, br s), 13.36(1H, br s)

MS (m/z): 354 (M⁺+2), 352 (M⁺, base)

Example 542-(2-Chloro-6-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-chloro-6-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 66, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.19 (2H, s), 7.2-7.3 (1H, m), 7.3-7.5(2H, m), 12.84 (1H, br s), 13.32 (1H, br s)

MS (m/z): 354 (M⁺+2), 352 (M⁺)

Example 552-{3,5-Bis(trifluoromethyl)benzyl}-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-{3,5-bis(trifluoromethyl)benzyl}-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 51, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.78 (3H, s), 4.24 (2H, s), 8.02 (1H, s), 8.11 (2H,s), 12.78 (1H, br s), 13.34 (1H, br s)

MS (m/z): 436 (M⁺)

Example 562-(3,4-Difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3,4-difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 52, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 3.99 (2H, s), 7.1-7.5 (3H, m), 12.75(1H, br s), 13.34 (1H, br s)

MS (m/z): 336 (M⁺)

Example 572-(2,5-Difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2,5-difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 53, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.06 (2H, s), 7.1-7.4 (3H, m), 12.79(1H, br s), 13.34 (1H, br s)

MS (m/z): 336 (M⁺)

Example 582-(2,4-Difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2,4-difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 65, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.03 (2H, s), 7.0-7.1 (1H, m), 7.2-7.3(1H, m), 7.4-7.5 (1H, m), 12.73 (1H, br s)

MS (m/z): 336 (M⁺)

Example 592-(2,6-Difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2,6-difluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 67, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 4.08 (2H, s), 7.1-7.2 (2H, m), 7.3-7.5(1H, m), 12.78 (1H, br s)

MS (m/z): 336 (M⁺)

Example 605-Methyl-4-oxo-2-(2,3,5-trifluorobenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(2,3,5-trifluorobenzyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 70, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.11 (2H, s), 7.1-7.3 (1H, m), 7.4-7.6(1H, m), 12.73 (1H, s)

MS (m/z): 354 (M⁺)

Example 615-Methyl-2-(naphthalen-1-ylmethyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(naphthalen-1-ylmethyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to Production Example 37, in the mannersimilar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.78 (3H, s), 4.45 (2H, s), 7.4-7.5 (1H, m), 7.5-7.6(3H, m), 7.8-7.9 (1H, m), 7.9-8.0 (1H, m), 8.13 (1H, d, J=8.3 Hz), 12.74(1H, br s)

MS (m/z): 350 (M⁺), 167 (base)

Example 622-(α-Hydroxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(α-hydroxybenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to Production Example 37, in the mannersimilar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.78 (3H, s), 5.59 (1H, s), 6.51 (1H, br s), 7.2-7.3(1H, m), 7.3-7.4 (2H, m), 7.52 (2H, d, J=7.3 Hz), 12.33 (1H, br s)

MS (m/z): 316 (M⁺), 298 (base)

Example 632-Benzhydryl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-benzhydryl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 37, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 5.52 (1H, s), 7.2-7.4 (10H, m), 12.82(1H, br s), 13.5 (1H, br s)

MS (m/z): 376 (M⁺, base)

Example 645-Methyl-4-oxo-2-(pyridin-2-ylmethyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(pyridin-2-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 36, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.81 (3H, s), 4.17 (2H, s), 7.2-7.5 (2H, m), 7.77(1H, dt, J=1.9, 7.7 Hz), 8.49 (1H, br s), 12.70 (1H, br s), 13.33 (1H,br s)

MS (m/z): 301 (M⁺, base)

Example 652-(Cyclopent-1-enylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(cyclopent-1-enylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 18, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 1.7-1.9 (2H, m), 2.2-2.4 (4H, m), 2.80 (3H, s), 3.41(2H, s), 5.48 (1H, s), 12.51 (1H, br s), 13.31 (1H, br s)

MS (m/z): 290 (M⁺)

Example 662-(Cyclohex-1-enylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(cyclohex-1-enylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized similarly to Production Example 18, in the manner similarto Example 1.

¹H-NMR (DMSO-d₆) δ: 1.4-1.5 (2H, m), 1.5-1.6 (2H, m), 1.9-2.0 (4H, m),2.77 (3H, s), 3.23 (2H, s), 5.52 (1H, s), 12.42 (1H, s)

MS (m/z): 304 (M⁺), 262 (base)

Example 672-Cyclopentylmethyl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-cyclopentylmethyl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 19, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 1.1-1.8 (8H, m), 2.2-2.4 (1H, m), 2.61 (2H, d, J=7.7Hz), 2.80 (3H, s), 12.44 (1H, br s), 13.29 (1H, br s)

MS (m/z): 292 (M⁺)

Example 682-Cyclohexylmethyl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-cyclohexylmethyl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 20, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 0.9-1.3 (5H, m), 1.5-1.9 (6H, m), 2.79 (3H, s),12.42 (1H, br s)

MS (m/z): 306 (M⁺)

Example 695-Methyl-4-oxo-2-piperidinomethyl-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

671 Milligrams of ethyl5-methyl-4-oxo-2-piperidinomethyl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylatewas suspended in 8 mL of 0.5N sodium hydroxide, stirred at 80° C. for 2hours, and allowed to cool off. The reaction liquid was neutralized with2N hydrochloric acid, and the precipitate was recovered by filtrationand dried, to provide 565 mg (92%) of the title compound.

¹H-NMR (DMSO-d₆) δ: 1.3-1.4 (2H, m), 1.5-1.6 (4H, m), 2.80 (3H, s), 3.44(2H, s)

MS (m/z): 307 (M⁺), 84 (base)

Example 705-Methyl-4-oxo-2-(4-oxopiperidinomethyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

Using ethyl2-chloromethyl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateand piperidin-4-one, a substitution reaction was carried out similarlyto later appearing Production Example 21. Successively the reactionproduct was hydrolyzed similarly to Example 33, without interveningisolation of the reaction product, to provide the title compound.

¹H-NMR (DMSO-d₆) δ: 2.78 (3H, s), 2.9-3.8 (10H, m)

Example 712-(4-Carboxypiperidinomethyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

Example 70 was repeated except that piperidin-4-one was replaced withethyl piperidine-4-carboxylate, to provide the title compound.

¹H-NMR (DMSO-d₆) δ: 1.6-1.8 (4H, m), 2.81 (3H, s), 3.1-3.2 (5H, m),3.4-3.5 (2H, m)

Example 725-Methyl-2-(1-decahydroquinolylmethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

Example 70 was repeated except that piperidin-4-one was replaced withdecahydroquinoline, to provide the title compound.

¹H-NMR (DMSO-d₆) δ: 1.7-2.0 (13H, m), 2.80 (3H, s)

Example 73 a: Synthesis of2-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

436 Milligrams of ethyl2-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 21 was suspended in 4 mL of 0.5Nsodium hydroxide and stirred at 100° C. for 2 hours. After cooling off,the reaction liquid was neutralized with 1N hydrochloric acid, and theprecipitate was recovered by filtration. Drying the same, 377 mg (92%)of the title compound was obtained.

b: Synthesis of5-methyl-4-oxo-2-(piperazin-1-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid Dihydrochloride

One-hundred (100) mg of the compound obtained in the above was dissolvedin 4N hydrochloric acid/dioxane solution, and stirred for 2.5 hours.Distilling the solvent off under reduced pressure, 96 mg (quantitative)of the title compound was obtained.

¹H-NMR (DMSO-d₆) δ: 2.78 (4H, br s), 2.80 (3H, s), 3.12 (4H, br s),3.5-3.7 (2H, m)

MS (m/z): 308 (M⁺), 85 (base)

Example 742-(Octahydropyrrolo[1,2-a]pyrazin-2-ylmethyl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

Example 70 was repeated except that piperidin-4-one was replaced withoctahydropyrrolo[1,2-a]pyrazine, to provide the title compound.

¹H-NMR (DMSO-d₆) δ: 1.7-1.8 (4H, m), 2.78 (3H, s), 2.9-3.1 (7H, m),3.4-3.6 (2H, m)

MS (m/z): 348 (M⁺), 96 (base)

Compounds of Examples 75-88 were obtained in the manner similar toExample 1, as follows.

Example 755-Methyl-4-oxo-2-phenyl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-phenyl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 60, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.89 (3H, s), 7.5-7.6 (3H, m), 8.1-8.2 (2H, m),12.69 (1H, br s)

MS (m/z): 286 (M⁺)

Example 765-Methyl-2-(2-naphthyl)-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(2-naphthyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 34, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.86 (3H, s), 7.5-7.7 (2H, m), 7.9-8.1 (3H, m), 8.23(1H, dd, J=1.5, 8.9 Hz), 8.82 (1H, s), 12.8 (1H, br s)

MS (m/z): 336 (M⁺), 139 (base)

Example 775-Methyl-4-oxo-2-(2-pyridyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(2-pyridyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to Production Example 60, in the mannersimilar to Example 1.

MS (m/z): 287 (M⁺, base)

Example 785-Methyl-4-oxo-2-(3-pyridyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(3-pyridyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to Production Example 60, in the mannersimilar to Example 1.

MS (m/z): 287 (M⁺), 243 (base)

Example 795-Methyl-4-oxo-2-(pyrazin-2-yl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(pyrazin-2-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to Production Example 60, in the mannersimilar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.84 (3H, s), 8.8-8.9 (1H, m), 8.88 (1H, d, J=2.7Hz), 9.48 (1H, s), 12.33 (1H, br s)

MS (m/z): 288 (M⁺, base)

Example 802-(2-Furyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(2-furyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to Production Example 60, in the mannersimilar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.81 (3H, s), 6.7-6.8 (1H, m), 7.65 (1H, dd, J=0.6,3.8 Hz), 8.0-8.1 (1H, m)

MS (m/z): 276 (M⁺, base)

Example 815-Methyl-4-oxo-2-(thiophen-3-yl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(thiophen-3-yl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 55, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.84 (3H, s), 7.7-7.8 (1H, m), 7.8-7.9 (1H, m), 8.66(1H, s), 12.35 (1H, br s), 12.66 (1H, br s)

MS (m/z): 292 (M⁺)

Example 825-Methyl-4-oxo-2-phenethyl-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-phenethyl-3,4-dihydrothino[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to the preceding Production Example, inthe manner similar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 2.8-3.1 (4H, m), 7.1-7.4 (5H, m),12.51 (1H, s)

MS (m/z): 314 (M⁺, base)

Example 835-Methyl-4-oxo-2-(β-oxophenethyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-(β-oxophenethyl)-3,4-dihydrothino[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to the preceding Production Example, inthe manner similar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 4.52 (2H, s), 7.5-8.1 (5H, m), 12.57(1H, s)

MS (m/z): 328 (M⁺), 105 (base)

Example 842-[2-(3-Chlorophenyl)-2-oxoethyl]-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-[2-(3-chlorophenyl)-2-oxoethyl]-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to the preceding Production Example, inthe manner similar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 4.55 (2H, s), 7.5-8.1 (4H, m), 12.58(1H, s)

MS (m/z): 364 (M⁺+2), 362 (M⁺), 139 (base)

Example 852-Butyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-butyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to the preceding Production Example, inthe manner similar to Example 1.

¹H-NMR (DMSO-d₆) δ: 1.2-1.4 (3H, m), 1.9-2.0 (4H, m), 2.79 (3H, s),12.46 (1H, s)

MS (m/z): 266 (M⁺), 224 (base)

Example 862-Allyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-allyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to the preceding Production Example, inthe manner similar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.5-2.6 (2H, m), 2.79 (3H, s), 3.1-3.5 (3H, m),12.46 (1H, s)

MS (m/z): 250 (M⁺, base)

Example 875-Methyl-2-methylthio-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-methylthio-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylatewhich was synthesized similarly to the preceding Production Example, inthe manner similar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.53 (3H, s), 2.76 (3H, s)

MS (m/z): 256 (M⁺)

Example 882-Carbamoylmethyl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-carbamoylmethyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylatewhich was synthesized similarly to the preceding Production Example, inthe manner similar to Example 1.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 3.52 (2H, s), 7.16 (1H, s), 7.58 (1H,s), 12.47 (1H, s)

MS (m/z): 267 (M⁺), 224 (base)

Example 892-(2-Aminoethyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid Hydrobromide

Using diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate and benzylN-(2-cyanoethyl)carbamate, the ring-closing reaction was carried outsimilarly to Production Example 1. Successively the hydrolysis wascarried out similarly to Example 1, to provide2-(2-benzyloxycarbonylaminoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid.

A mixture of 387 mg of so obtained2-(2-benzyloxycarbonyl-aminoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid and 4.5 mL of hydrobromic acid was stirred at room temperature for3 hours, and thereafter the solvent was distilled off under reducedpressure to provide 410 mg (quantitative) of the title compound.

¹H-NMR (DMSO-d₆) δ: 2.80 (3H, s), 2.9-3.0 (2H, m), 3.2-3.3 (2H, m), 7.80(2H, br s), 12.58 (1H, br s)

MS (m/z): 253 (M⁺)

Example 905-Methyl-4-oxo-2-phenoxy-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-phenoxy-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 61, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.79 (3H, s), 7.2-7.5 (5H, m)

MS (m/z): 302 (M⁺)

Example 915-Methyl-4-oxo-2-phenylthio-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-phenylthio-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized similarly to Production Example 61, in the manner similarto Example 1.

¹H-NMR (DMSO-d₆) δ: 2.77 (3H, s), 7.4-7.7 (5H, m), 13.02 (1H, br s),13.29 (1H, br s)

MS (m/z): 318 (M⁺)

Example 925-Methyl-4-oxo-2-phenylamino-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-oxo-2-phenylamino-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 68, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.68 (1.2H, s), 2.70 (0.3H, s), 2.76 (1.5H, s),7.3-7.6 (5H, m), 9.63 (0.5H, s), 11.16 (0.1H, s), 11.22 (0.4H, br s),12.89 (1H, br s)

MS (m/z): 301 (M⁺)

Example 933-Benzyl-2,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl3-benzyl-2,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 22, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.23 (3H, s), 2.80 (3H, s), 5.32 (2H, s), 7.2-7.4(5H, m)

MS (m/z): 314 (M⁺), 91 (base)

Example 942-(3,4-Dichlorobenzyl)-3,5-dimethyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3,4-dichlorobenzyl)-3,5-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 23, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.44 (3H, s), 2.78 (3H, s), 3.88 (2H, s), 7.2-7.4(1H, m), 7.5-7.6 (2H, m)

MS (m/z): 384 (M⁺+2), 382 (M⁺)

Example 953-Methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-2-carboxylicacid

75 Milligrams of ethyl3-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-6-carboxylatewas suspended in a liquid mixture of 0.5 mL of ethanol, 1 mL of waterand 1 mL of 1N aqueous sodium hydroxide solution, and stirred at about100° C. for 2 hours. Thereafter 0.35 mL of 3N hydrochloric acid wasadded to the reaction mixture, to adjust the pH to 5. Distilling themixture under reduced pressure, adequate amounts of chloroform andmethanol were added to the residue to precipitate inorganic salts. Theprecipitated inorganic salts were removed by filtration and the filtratewas condensed under reduced pressure. Solidifying the residue byaddition of hexane, 50 mg (74%) of the title compound was obtained.

¹H-NMR (DMSO-d₆) δ: 1.8-1.9 (2H, m), 2.0-2.1 (2H, m), 2.74 (3H, s), 2.77(2H, t, J=6.6 Hz), 4.1-4.4 (2H, m)

MS (m/z): 264 (M⁺)

Example 962-(3,4-Dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-aceticAcid

92 Milligrams of butyl2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-acetateas synthesized in Production Example 25 was suspended in 1 mL of waterand to which 0.63 mL of 1N aqueous sodium hydroxide solution was added,followed by an hour's stirring at about 70° C. Then the reaction mixturewas neutralized with 0.63 mL of 1N hydrochloric acid, and the resultingprecipitate was recovered by filtration and dried to provide 87 mg(quantitative) of the title compound.

¹H-NMR (DMSO-d₆) δ: 2.38 (3H, s), 3.77 (2H, s), 3.95 (2H, s), 7.3-7.4(1H, m), 7.58 (1H, d, J=8.1 Hz), 7.63 (1H, d, J=1.9 Hz), 12.46 (1H, s)

MS (m/z): 384 (M⁺+2), 382 (M⁺)

The compounds of Examples 97-116 were synthesized in the manner similarto Example 1.

Example 972-(3,4-Dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-propionicAcid

The title compound was synthesized from ethyl2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-propionateas synthesized in Production Example 27, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 2.39 (3H, s), 2.97 (2H, t, J=7.3 Hz), 3.95 (2H, s),7.2-7.7 (3H, m), 12.24 (1H, br s), 12.44 (1H, br s)

MS (m/z): 398 (M⁺+2), 396 (M⁺)

Example 982-(3,4-Dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-butyricacid

The title compound was synthesized from ethyl2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-butyrateas synthesized in Production Example 29, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 1.7-1.9 (2H, m), 2.27 (2H, t, J=7.3 Hz), 2.37 (3H,s), 2.76 (2H, t, J=7.7 Hz), 3.95 (2H, s), 7.2-7.7 (3H, m), 12.08 (1H, brs), 12.43 (1H, br s)

MS (m/z): 412 (M⁺+2), 410 (M⁺)

Example 992-(3,4-Dichlorobenzyl)-4-oxo-5-trifluoromethyl-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3,4-dichlorobenzyl)-4-oxo-5-trifluoromethyl-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 31, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 4.03 (2H, s), 7.3-7.7 (3H, m), 12.99 (1H, br s)

MS (m/z): 424 (M⁺+2), 422 (M⁺)

Example 1002-(3,4-Dichlorobenzyl)-5-methoxymethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3,4-dichlorobenzyl)-5-methoxymethyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 33, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 3.71 (2H, s), 3.90 (3H, s), 3.94 (2H, s), 7.2-7.7(3H, m), 12.18 (1H, br s), 12.48 (1H, br s)

MS (m/z): 400 (M⁺+2), 398 (M⁺)

Example 1014-Oxo-2-(thiophen-3-ylmethyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl4-oxo-2-(thiophen-3-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 77, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 4.00 (2H, s), 7.10 (1H, dd, J=1.5, 5.0 Hz), 7.3-7.4(1H, m), 7.49 (1H, dd, J=3.0, 5.0 Hz), 7.83 (1H, s), 12.83 (1H, s),13.52 (1H, br s)

MS (m/z): 292 (M⁺)

Example 1024-Oxo-2-(thiophen-2-ylmethyl)-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl4-oxo-2-(thiophen-2-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized similarly to Production Example 77, in the manner similarto Example 1.

¹H-NMR (DMSO-d₆) δ: 4.20 (2H, s), 6.99 (1H, dd, J=3.5, 5.3 Hz), 7.0-7.1(1H, m), 7.42 (1H, dd, J=1.2, 5.0 Hz), 7.85 (1H, s), 12.89 (1H, s),13.57 (1H, br s)

MS (m/z): 292 (M⁺)

Example 1032-Benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid

The title compound was synthesized from ethyl2-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate assynthesized in Production Example 45, in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 3.99 (2H, s), 7.2-7.4 (5H, m), 7.84 (1H, s), 12.87(1H, br s), 13.56 (1H, br s)

MS (m/z): 286 (M⁺), 169 (base)

Example 1042-(3-Chlorobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-chlorobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 76, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 4.01 (2H, s), 7.3-7.4 (3H, m), 7.4-7.5 (1H, m), 7.84(1H, s), 12.87 (1H, s), 13.50 (1H, br s)

MS (m/z): 320 (M⁺)

Example 1054-Oxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl4-oxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 79, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 4.11 (2H, s), 7.5-7.7 (3H, m), 7.77 (1H, s), 7.84(1H, s), 12.89 (1H, s), 13.58 (1H, br s)

MS (m/z): 354 (M⁺)

Example 1062-(3,4-Dichlorobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3,4-dichlorobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 46, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 4.02 (2H, s), 7.36 (1H, dd, J=1.9, 8.3 Hz), 7.60(1H, d, J=8.3 Hz), 7.66 (1H, d, J=1.9 Hz), 7.85 (1H, s), 12.85 (1H, brs), 13.57 (1H, br s)

MS (m/z): 356 (M⁺+2), 354 (M⁺), 169 (base)

Example 1072-(Cyclopent-1-enylmethyl)-4-oxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(cyclopent-1-enylmethyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 78, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 1.3-1.4 (2H, m), 2.2-2.4 (4H, m), 3.44 (2H, s),5.4-5.5 (1H, m), 7.85 (1H, s), 12.66 (1H, s), 13.55 (1H, br s)

MS (m/z): 276 (M⁺)

Example 1085-Methyl-2-(thiophen-3-ylmethyl)-4-thioxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(thiophen-3-ylmethyl)-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 87, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 3.05 (3H, s), 4.10 (2H, s), 7.10 (1H, dd, J=1.2, 5.0Hz), 7.3-7.4 (1H, m), 7.4-7.6 (1H, m), 13.57 (1H, br s), 13.94 (1H, brs)

MS (m/z): 322 (M⁺, base)

Example 1095-Methyl-2-(thiophen-2-ylmethyl)-4-thioxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-2-(thiophen-2-ylmethyl)-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 85, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 3.05 (3H, s), 4.31 (2H, s), 6.99 (1H, dd, J=3.5, 5.0Hz), 7.05 (1H, dd, J=1.3, 3.5 Hz), 7.43 (1H, dd, J=1.3, 5.0 Hz), 13.59(1H, br s), 14.00 (1H, br s)

MS (m/z): 322 (M⁺), 97 (base)

Example 1102-Benzyl-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-benzyl-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 91, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 3.05 (3H, s), 4.10 (2H, s), 7.2-7.4 (5H, m), 13.56(1H, br s), 13.98 (1H, br s)

MS (m/z): 316 (M⁺, base)

Example 1112-(3-Bromobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-bromobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 83, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 3.05 (3H, s), 4.11 (2H, s), 7.2-7.4 (2H, m), 7.4-7.5(1H, m), 7.5-7.7 (1H, m), 13.58 (1H, br s), 13.97 (1H, br s)

MS (m/z): 396 (M⁺+2, base), 394 (M⁺)

Example 1122-(3-Chlorobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-chlorobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 93, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 3.05 (3H, s), 4.12 (2H, s), 7.2-7.5 (4H, m), 13.57(1H, br s), 13.97 (1H, br s)

MS (m/z): 352 (M⁺+2), 350 (M⁺, base)

Example 1135-Methyl-4-thioxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl5-methyl-4-thioxo-2-(trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 97, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 3.05 (3H, s), 4.22 (2H, s), 7.5-7.7 (3H, m), 7.78(1H, s), 13.58 (1H, br s), 14.00 (1H, br s)

MS (m/z): 384 (M⁺, base)

Example 1142-(3,4-Dichlorobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3,4-dichlorobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylateas synthesized in Production Example 81, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 3.05 (3H, s), 4.13 (2H, s), 7.35 (1H, dd, J=1.9, 8.3Hz), 7.60 (1H, d, J=8.3 Hz), 7.67 (1H, d, J=1.9 Hz), 13.57 (1H, br s),14.96 (1H, br s)

MS (m/z): 386 (M⁺+2), 384 (M⁺, base)

Example 1152-(3-Chloro-4-fluorobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3-chloro-4-fluorobenzyl)-5-methyl-4-thioxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 95, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 3.05 (3H, s), 4.11 (2H, s), 7.3-7.5 (2H, m), 7.5-7.7(1H, m), 13.59 (1H, br s), 13.97 (1H, br s)

MS (m/z): 370 (M⁺+2), 368 (M⁺, base)

Example 1162-(Cyclohex-1-enylmethyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(cyclohex-1-enylmethyl)-5-methyl-4-thioxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 89, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 1.4-1.7 (4H, m), 1.8-2.1 (4H, m), 3.06 (3H, s), 3.39(2H, s), 5.53 (1H, s), 13.56 (1H, br s), 13.72 (1H, br s)

MS (m/z): 320 (M⁺, base)

Example 1172-(Cyclopent-1-enylmethyl)-5-methyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid and2-cyclopentylidenemethyl-5-methyl-4-thioxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid

After carrying out the operations similar to Production Example 80, theresulting crystals were subjected to the operations similar toProduction Example 81. Further following Example 1, the title compoundswere obtained as a mixture.

Cyclopent-1-enylmethyl Form:

¹H-NMR (DMSO-d₆) δ: 1.7-1.9 (2H, m), 2.2-2.4 (4H, m), 3.06 (3H, s), 3.54(2H, s), 5.4-5.5 (1H, m), 13.47 (1H, br s), 13.77 (1H, br s)

Cyclopentylidenemethyl Form:

¹H-NMR (DMSO-d) δ: 1.6-1.9 (4H, m), 2.4-2.7 (2H, m), 2.8-2.9 (2H, m),3.06 (3H, s), 6.4-6.5 (1H, m), 13.47 (1H, br s), 13.77 (1H, br s)

MS (m/z): 314 (M⁺)

The compounds of Examples 118-119 were synthesized in the manner similarto Example 1.

Example 1182-Benzyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid

The title compound was synthesized from ethyl2-benzyl-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate assynthesized in Production Example 101, in the manner similar to Example1.

¹H-NMR (DMSO-d₆) δ: 4.13 (2H, s), 7.2-7.4 (5H, m), 8.00 (1H, s), 13.77(1H, br s), 14.26 (1H, br s)

MS (m/z): 302 (M⁺, base)

Example 1192-(3,4-Dichlorobenzyl)-4-thioxo-3,4-dihydrothieno[2,3-d]-pyrimidine-6-carboxylicacid

The title compound was synthesized from ethyl2-(3,4-dichlorobenzyl)-4-thioxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylateas synthesized in Production Example 99, in the manner similar toExample 1.

¹H-NMR (DMSO-d₆) δ: 4.16 (2H, s), 7.35 (1H, dd, J=1.9, 8.3 Hz), 7.61(1H, d, J=8.3 Hz), 7.67 (1H, d, J=1.9 Hz), 8.01 (1H, s), 13.77 (1H, brs), 14.22 (1H, br s)

MS (m/z): 372 (M⁺+2), 370 (M⁺, base)

Formulation Example Tablets

mg/tablet Active ingredient 5.0 Starch 10.0 Lactose 73.0 Carboxymethylcellulose calcium 10.0 Talc 1.0 Magnesium stearate 1.0 100.0

The active ingredient was pulverized to grain sizes not greater than 70μm, to which starch, lactose and carboxymethyl cellulose calcium wereadded and thoroughly mixed. Then 10% starch paste was added to thepowdery mixture and mixed by stirring to provide granules. After dryingthem, their grain sizes were dressed to around 1,000 μm, with which talcand magnesium stearate were mixed. The mixture was tabletted.

1. A compound represented by the following formula (I)

in which R¹ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxyC₁₋₆ alkyl or C₁₋₆haloalkyl containing 1-6 halogen atoms, R² is hydrogen, C₁₋₆ alkyl,phenylC₁₋₆ alkyl or amino, R³ is C₂₋₆ alkyl, C₂₋₆ alkenyl, carbamoylC₁₋₆alkyl, aminoC₁₋₆ alkyl, C₁₋₆ alkylaminoC₁₋₆ alkyl, di-(C₁₋₆alkyl)aminoC₁₋₆ alkyl, C₁₋₆ alkylthio or Y—X— group, or R² and R³ maytogether form tetramethylene, X is a direct bond, or CH₂, CH(OH),CH(C₆H₅), CO, CH₂CH₂, CH₂CO, COCH₂, S, O or NH and Y is an aromaticcarbocyclic group, aromatic heterocyclic group, 4-7-membered cycloalkylgroup, 4-7-membered cycloalkenyl group, 5-7-membered saturatedheterocyclic group containing 1 or 2 nitrogen atoms, or 5-7-memberedsaturated heterocyclic group forming a condensed ring with 5 or6-membered saturated cyclic group and containing 1 or 2 nitrogen atoms,all of these groups optionally containing 1-3 substituents selected fromthe group consisting of halogen atom, C₁₋₆ alkyl, C₁₋₆ haloalkylcontaining 1-6 halogen atoms, C₁₋₆ haloalkyloxy containing 1-6 halogenatoms, C₁₋₆ haloalkylthio containing 1-6 halogen atoms, C₁₋₆ alkoxy,C₁₋₆ alkylthio, C₁₋₄ alkylenedioxy, carboxyl, C₁₋₆ alkoxycarbonyl, oxo,amino, nitro and phenyl, Z is S or O, and n is 0 or an integer of 1-4,with the proviso that a case wherein R¹ is methyl, R² is hydrogen, R³ isbenzyl, Z is O and n is 0 is excluded, or a salt thereof.
 2. Thecompound or salt thereof according to claim 1, in which R¹ is C₁₋₆alkyl.
 3. The compound or salt thereof according to claim 1, in which R²is hydrogen.
 4. The compound or salt thereof according to claim 1, inwhich R³ is Y—X— group.
 5. The compound or salt thereof according toclaim 4, in which X is CH₂, S, O or NH.
 6. The compound or salt thereofaccording to claim 4, in which Y is an aromatic carbocyclic group oraromatic heterocyclic group, which are optionally substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl containing 1-6 halogen atoms, C₁₋₆ haloalkyloxycontaining 1-6 halogen atoms, C₁₋₆ haloalkylthio containing 1-6 halogenatoms, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₄ alkylenedioxy, carboxyl, C₁₋₆alkoxycarbonyl, amino, nitro and phenyl.
 7. The compound or salt thereofaccording to claim 1, in which Z is O.
 8. The compound or salt thereofaccording to claim 1, in which n is
 0. 9. A method of treating anoveractive bladder syndrome, pollakiuria, urinary incontinence orlearning and/or memory cognitive impairment, which comprisesadministering a therapeutically effective amount of a compound accordingto claim 1 or salt thereof to a patient in need thereof.
 10. A methodfor preparing a pharmaceutical composition, which comprises combining acompound according to claim 1 or salt thereof with a pharmaceuticallyacceptable carrier.
 11. A pharmaceutical composition comprising thecompound according to claim 1 or salt thereof, and a pharmaceuticallyacceptable carrier. 12.2-(3,4-Dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid or a salt thereof. 13.2-(3-Chlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid or a salt thereof. 14.5-Methyl-4-oxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid or a salt thereof. 15.2-(3-Chloro-4-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid or a salt thereof. 16.2-(5-Chloro-2-fluorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid or a salt thereof. 17.2-(Cyclopent-1-enylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid or a salt thereof. 18.4-Oxo-2-(thiophen-2-ylmethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid or a salt thereof. 19.2-Benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid or asalt thereof. 20.2-(3-Chlorobenzyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylicacid or a salt thereof. 21.4-Oxo-2-(3-trifluoromethylbenzyl)-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylicacid or a salt thereof.